Archive for the ‘Skin Stem Cells’ Category

Mouse and human skin cells can be reprogrammed to hunt down tumors and deliver anticancer therapies.

Imagine cells that can move through your brain, hunting down cancer and destroying it before they themselves disappear without a trace. Scientists have just achieved that in mice, creating personalized tumor-homing cells from adult skin cells that can shrink brain tumors to 2% to 5% of their original size. Althoughthe strategy has yet to be fully tested in people, the new method could one day give doctors a quick way to develop a custom treatment for aggressive cancers like glioblastoma, which kills most human patients in 1215 months. It only took 4 days to create the tumor-homing cells for the mice.

Glioblastomas are nasty: They spread roots and tendrils of cancerous cells through the brain, making them impossible to remove surgically. They, and other cancers, also exude a chemical signal that attracts stem cellsspecialized cells that can produce multiple cell types in the body. Scientists think stem cells might detect tumors as a wound that needs healing and migrate to help fix the damage. But that gives scientists a secret weaponif they can harness stem cells natural ability to home toward tumor cells, the stem cells could be manipulated to deliver cancer-killing drugs precisely where they are needed.

Other research has already exploited this methodusing neural stem cellswhich give rise to neurons and other brain cellsto hunt down brain cancer in mice and deliver tumor-eradicating drugs. But few have tried this in people, in part because getting those neural stem cells is hard, says Shawn Hingtgen, a stem cell biologist at the University of North Carolina inChapel Hill. Right now, there are three main ways. Scientists can either harvest the cells directly from the patient, harvest them from another patient, or they can genetically reprogram adult cells. But harvesting requires invasive surgery, and bestowing stem cell properties on adult cells takes a two-step process that can increase the risk of the final cells becoming cancerous. And using cells from someone other than the cancer patient being treated might trigger an immune response against the foreign cells.

To solve these problems, Hingtgens group wanted to see whetherthey could skip a step in the genetic reprogramming process, which first transforms adult skin cells into standard stem cells and then turns those into neural stem cells. Treating the skin cells with a biochemical cocktail to promote neural stem cell characteristics seemed to do the trick, turning it into a one-step process, he and his colleague report today in Science Translational Medicine.

But the next big question was whether these cells could home in on tumors in lab dishes, and in animals, like neural stem cells. We were really holding our breath, Hingtgen says. The day we saw the cells crawling across the [Petri] dish toward the tumors, we knew we had something special. The tumor-homing cells moved 500 micronsthe same width as five human hairsin 22 hours, and they could burrow into lab-grown glioblastomas. This is a great start, says Frank Marini, a cancer biologist at the Wake Forest Institute forRegenerative Medicine in Winston-Salem, North Carolina,who was not involved with the study. Incredibly quick and relatively efficient.

The team also engineered the cells to deliver common cancer treatments to glioblastomas in mice. Mouse tumors injected directly with the reprogrammed stem cells shrank 20- to 50-fold in 2428 days compared withnontreated mice. In addition, the survival times of treated rodents nearly doubled. In some mice, the scientists removed tumors after they were established, and injected treatment cells into the cavity. Residual tumors, spawned from the remaining cancer cells, were 3.5 times smaller in the treated mice than in untreated mice.

Marini notes that more rigorous testing is needed to demonstrate just how far the tumor-targeting cells can migrate. In a human brain, the cells would need to travel a matter of millimeters or centimeters, up to 20 times farther than the 500 microns tested here, he says. And other researchers question the need to use cells from the patients own skin. An immune response, triggered by foreign neural stem cells, could actually help attack tumors, says Evan Snyder, a stem cell biologist at Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, and one of the early pioneers of the idea of using stem cells to attack tumors.

Hingtgens group is already testing how far their tumor-homing cells can migrate using larger animal models. They are also getting skin cells from glioblastoma patients to make sure the new method works for the people they hope to help, he says. Everything were doing is to get this to the patient as quickly as we can.

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Reprogrammed skin cells shrink brain tumors in mice - Science Magazine

Glioblastoma is an aggressive form of brain cancer that kills most patients within two years of diagnosis. In tests on mice last year, a team at the University of North Carolina at Chapel Hill showed that adult skin cells could be transformed into stem cells and used to hunt down the tumors. Building on that, they've now found that the process works with human cells, and can be administered quickly enough to beat the ticking time-bombs.

Treatments for glioblastoma include the usual options of surgery, radiation therapy and chemotherapy, but none of them are particularly effective. The tumors are capable of spreading tendrils out into the brain and it can grow back in a matter of months after being removed. As a result, the median survival rate of sufferers is under 18 months, and there's only a 30 percent chance of living more than two years.

"We desperately need something better," says Shawn Hingtgen, the lead researcher on the study.

To find that something better, last year the scientists took fibroblasts a type of skin cell that generates collagen and connective tissue from mice and reprogrammed them into neural stem cells. These stem cells seek out and latch onto cancer cells in the brain, but alone are powerless to fight the tumor. To give them that ability, the scientists engineered them to express a particular cancer-killing protein. The result was mice that lived between 160 and 220 percent longer.

The next step was to test the process with human cells, and in the year since, the team has found that the results are just as promising. The technique differs slightly when scaled up to humans. The patient would be administered with a substance called a prodrug, which by itself does nothing, until it's triggered. The stem cells are engineered to carry a protein that acts as that trigger, activating the prodrug only in a small halo around itself instead of affecting the entire body. That allows the drug to target only a small desired area, ideally reducing the ill side effects that treatments like chemotherapy can induce.

Importantly, the technique can be administered quickly, to give the patients the best chance at survival.

"Speed is essential," says Hingtgen. "It used to take weeks to convert human skin cells to stem cells. But brain cancer patients don't have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient."

The treatment is an important step, but there's still a long way to go.

"We're one to two years away from clinical trials, but for the first time, we showed that our strategy for treating glioblastoma works with human stem cells and human cancers," says Hingtgen. "This is a big step toward a real treatment and making a real difference."

The research was published in the journal Science Translational Medicine.

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Stem cells beat the clock for brain cancer - New Atlas

Brain cancers can be really tricky to treat. Some, such as glioblastomas, spread roots through the brain tissue, meaning they are often impossible to remove surgically, leading to tragically low survival rates. But researchers are working on a way touse stem cells to track down the cancer, kill it, and then melt it away. By doing this, theyve managed to shrink brain tumors in mice to2 to 5 percent of their original size.

The trick has already been tried before using neural stem cells to hunt down and deliver cancer-killing drugs to tumors in mice. But there is a problem: It's tricky to getneural stem cells from humans. The safest way of doing this would be to take adult cells and then induce them in a two-step process to become neural stem cells. This, however, takes time.

Speed is essential, saysShawn Hingtgen, who led the research published in Science Translational Medicine. It used to take weeks to convert human skin cells to stem cells. But brain cancer patients dont have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient.

The researchers found a way to speed the process up byremoving one of the steps entirely, allowing them to produce the neural stem cells from adult skin cells in just four days. Usually, researchers would need to take the skin cell, induce it to become a generic stem cell, and then push it towards becoming a neural stem cell.

But by treating the skin cells with a cocktail of biochemicals, they were able to get the cells to turn straight into neural stem cells. They then tested these to see if they still had the same properties as original neutral stem cells and home in on tumors both in a petri dish and in animals models. They found they behaved exactly the same.

The final step was to see if they could somehow engineer these newly created cells to deliver drugs that are targeted at the cancer. They therefore got the stem cells to carry a particular protein that activates what is called a prodrug, which the researchers describe as forming a halo of drugs around the stem cell.

Were one to two years away from clinical trials, but for the first time, we showed that our strategy for treating glioblastoma works with human stem cells and human cancers, says Hingtgen. This is a big step toward a real treatment and making a real difference.

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Scientists Reprogram Skin Cells To Hunt Down And Shrink Brain Tumors - IFLScience

IRVINE, Calif., Feb. 7, 2017 /PRNewswire/ --AIVITA Biomedical today announced it will present details of its patented skin care technology and commercial line of skin care products at the upcoming South Beach Symposium in Miami Beach, Florida. The conference, taking place February 9-12 at the Loews Hotel Miami Beach, will be attended by physicians and practitioners seeking the latest therapies, technologies and procedures in medical and aesthetic skin care.

The South Beach Symposium is a 4-day conference which offers multiple educational tracks allowing medical professionals from both clinical and aesthetic dermatology practices to participate in focused education. AIVITA's Chief Executive Officer, Hans S. Keirstead, Ph.D., will meet with key opinion leaders to discuss AIVITA's new product lines. AIVITA's Chief Science Officer, Gabriel Nistor, M.D., will lead a Continuing Medical Education course in Thursday's session "Anti-Aging Medicine for the Dermatologist." Dr. Nistor's course, titled Stem Cells and Growth Factors in Skin Rejuvenation, will detail advancements in the understanding and application of human stem cell-derived growth factors for skin rejuvenation. On Friday, AIVITA Biomedical Scientific Advisory Board member Dr. Zoe Draelos, M.D. will chair a special symposium, "The Science of Topical Therapy, RX, OTC and Cosmeceuticals," in which she will present research she conducted on AIVITA's skin care advancements. The company will also have a scientific poster on display highlighting the findings of a clinical study which demonstrated improvements in several key areas of visible skin aging using the company's proprietary formulation.

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AIVITA Biomedical to Present Skin Care Technology and Products at 15th Annual South Beach Symposium - PR Newswire (press release)

Stem cells have tremendous promise to help us understand and treat a range of diseases, injuries and other health-related conditions. Their potential is evident in the use of blood stem cells to treat diseases of the blood, a therapy that has saved the lives of thousands of children with leukemia; and can be seen in the use of stem cells for tissue grafts to treat diseases or injury to the bone, skin and surface of the eye. Important clinical trials involving stem cells are underway for many other conditions and researchers continue to explore new avenues using stem cells in medicine.

There is still a lot to learn about stem cells, however, and their current applications as treatments are sometimes exaggerated by the media and other parties who do not fully understand the science and current limitations, and also by clinics looking to capitalize on the hype by selling treatments to chronically ill or seriously injured patients. The information on this page is intended to help you understand both the potential and the limitations of stem cells at this point in time, and to help you spot some of the misinformation that is widely circulated by clinics offering unproven treatments.

It is important to discuss these Nine Things to Know and any research or information you gather with your primary care physician and other trusted members of your healthcare team in deciding what is right for you.

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Nine Things to Know About Stem Cell Treatments

3D printing may seem a little unfathomable to some, especially when you apply biomedical engineering to 3D printing. In general, 3D printing involves taking a digital model or blueprint created via software, which is then printed in successive layers of materials like glass, metal, plastic, ceramic and assembled one layer at a time. Many major manufacturers use them to manufacture airplane parts or electrical appliances.

Some of the most incredible uses for 3D printing are developing within the medical field. Some of the following ways this futuristic technology is being developed for medical use might sound like a Michael Crichton novel, but are fast becoming reality.

Bioprinting is based on bio-ink, which is made of living cell structures. When a particular digital model is input, specific living tissue is printed and built up layer by cell layer. Bioprinting research is being developed to print different types of tissue, while 3D inkjet printing is being used to develop advanced medical devices and tools.

While an entire organ has yet to be successfully printed for practical surgical use, scientists and researchers have successfully printed kidney cells, sheets of cardiac tissue that beat like a real heart and the foundations of a human liver, among many other organ tissues. While printing out an entire human organ for transplant may still be at least a decade away, medical researchers and scientists are well on their way to making this a reality.

Stem cells have amazing regenerative properties already they can reproduce many different kinds of human tissue. Now, stem cells are being bioprinted in several university research labs, such as the Heriot-Watt University of Edinburgh. Stem cell printing was the precursor to printing other kinds of tissues, and could eventually lead to printing cells directly into parts of the body.

Imagine the uses that printing skin grafts could do for burn victims, skin cancer patients and other kinds of afflictions and diseases that affect the epidermis. Medical engineers in Germany have been developing skin cell bioprinting since 2010, and researcher James Yoo from Wake Forest Institute is developing skin graft printing that can be applied directly onto burn victims.

Hod Lipson, a Cornell engineer, prototyped tissue bioprinting for cartilage within the past few years. Though Lipson has yet to bioprint a meniscus that can withstand the kind of pressure and pounding that a real one can, he and other engineers are well on their way to understanding how to apply these properties. Additionally, the same group from Germany who bioprinted stem cells is also working toward the same results for bioprinting bone and others parts of the skeletal system.

Just six months ago, bioengineering students from the University of British Columbia won a prestigious award for their engineering and 3D printing of a new and extremely effective type of surgical smoke evacuator. Other surgical tools that have been 3D printed include forceps, hemostats, scalpel handles and clamps and best of all, they come out of the printer sterile and cost a tenth as much as the stainless steel equivalent.

In the same way that tissue and types of organ cells are being printed and studied, disease cells and cancer cells are also being bioprinted, in order to more effectively and systematically study how tumors grow and develop. Such medical engineering would allow for better drug testing, cancer cell analyzing and therapy development. With developments in 3D and bioprinting, it may even be a possibility within our lifetime that a cure for cancer is discovered.

Another German institute has created blood vessels using artificial biological cells, a 3D inkjet printer and a laser to mold them into shape. Likewise, researchers at the University of Rostock in Germany, Harvard Medical Institute and the University of Sydney are developing methods of heart repair, or types of a heart patch, made with 3D printed cells.

The human cell heart patches have gone through successful testing on rats, and have also included development of artificial cardiac tissues that successfully mimic the mechanical and biological properties of a real human heart.

There are plenty of other developments being made with 3D and bioprinting, but one of the biggest obstacles is finding software that is advanced or sophisticated enough to meet the challenge of creating the blueprint. While creating the blueprint for an ash tray, and subsequently producing it via 3D printing is a fairly simple and quick process, there is no equivalent for creating digital models of a liver or heart at this point.

However, with the quick developments and advancements researchers and biomedical engineers have made in a short few years, this obstacle will soon be one of many that are overcome on the way to successful complex bioprinting.

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Actin is a family of globular multi-functional proteins that form microfilaments. It is found in essentially all eukaryotic cells (the only known exception being nematode sperm), where it may be present at a concentration of over 100 M. An actin protein's mass is roughly 42-kDa, with a diameter of 4 to 7nm, and it is the monomeric subunit of two types of filaments in cells: microfilaments, one of the three major components of the cytoskeleton, and thin filaments, part of the contractile apparatus in muscle cells. It can be present as either a free monomer called G-actin (globular) or as part of a linear polymer microfilament called F-actin (filamentous), both of which are essential for such important cellular functions as the mobility and contraction of cells during cell division.

Actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes.[2] In vertebrates, three main groups of actin isoforms, alpha, beta, and gamma have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of tropomyosin along the filaments.[3]

A cells ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organisms internal signals, for example, to increase cell membrane absorption or increase cell adhesion in order to form cell tissue. Other enzymes or organelles such as cilia can be anchored to this scaffolding in order to control the deformation of the external cell membrane, which allows endocytosis and cytokinesis. It can also produce movement either by itself or with the help of molecular motors. Actin therefore contributes to processes such as the intracellular transport of vesicles and organelles as well as muscular contraction and cellular migration. It therefore plays an important role in embryogenesis, the healing of wounds and the invasivity of cancer cells. The evolutionary origin of actin can be traced to prokaryotic cells, which have equivalent proteins.[4] Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea.[5] Lastly, actin plays an important role in the control of gene expression.

A large number of illnesses and diseases are caused by mutations in alleles of the genes that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of infection by some pathogenic microorganisms. Mutations in the different genes that regulate actin production in humans can cause muscular diseases, variations in the size and function of the heart as well as deafness. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular bacteria and viruses, particularly in the processes related to evading the actions of the immune system.[6]

Actin was first observed experimentally in 1887 by W.D. Halliburton, who extracted a protein from muscle that 'coagulated' preparations of myosin that he called "myosin-ferment".[7] However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to Brun Ferenc Straub, a young biochemist working in Albert Szent-Gyrgyi's laboratory at the Institute of Medical Chemistry at the University of Szeged, Hungary.

In 1942, Straub developed a novel technique for extracting muscle protein that allowed him to isolate substantial amounts of relatively pure actin. Straub's method is essentially the same as that used in laboratories today. Szent-Gyorgyi had previously described the more viscous form of myosin produced by slow muscle extractions as 'activated' myosin, and, since Straub's protein produced the activating effect, it was dubbed actin. Adding ATP to a mixture of both proteins (called actomyosin) causes a decrease in viscosity. The hostilities of World War II meant Szent-Gyorgyi and Straub were unable to publish the work in Western scientific journals. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the Acta Physiologica Scandinavica.[8] Straub continued to work on actin, and in 1950 reported that actin contains bound ATP[9] and that, during polymerization of the protein into microfilaments, the nucleotide is hydrolyzed to ADP and inorganic phosphate (which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in smooth muscle, and was not supported through experimentation until 2001.[9][10]

The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973.[11] The crystal structure of G-actin was solved in 1990 by Kabsch and colleagues.[12] In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins.[13] The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of F-actin was possible due to the use of a rhodamine conjugate that impedes polymerization by blocking the amino acid cys-374.[1] Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time.[14]

Although no high-resolution model of actins filamentous form currently exists, in 2008 Sawayas team were able to produce a more exact model of its structure based on multiple crystals of actin dimers that bind in different places.[15] This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of cryo-electron microscopy and synchrotron radiation have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.[16][17][18]

Its amino acid sequence is also one of the most highly conserved of the proteins as it has changed little over the course of evolution, differing by no more than 20% in species as diverse as algae and humans. It is therefore considered to have an optimised structure.[4] It has two distinguishing features: it is an enzyme that slowly hydrolizes ATP, the "universal energy currency" of biological processes. However, the ATP is required in order to maintain its structural integrity. Its efficient structure is formed by an almost unique folding process. In addition, it is able to carry out more interactions than any other protein, which allows it to perform a wider variety of functions than other proteins at almost every level of cellular life.[4]Myosin is an example of a protein that bonds with actin. Another example is villin, which can weave actin into bundles or cut the filaments depending on the concentration of calcium cations in the surrounding medium.[19]

Actin is one of the most abundant proteins in eukaryotes, where it is found throughout the cytoplasm.[19] In fact, in muscle fibres it comprises 20% of total cellular protein by weight and between 1% and 5% in other cells. However, there is not only one type of actin, the genes that code for actin are defined as a gene family (a family that in plants contains more than 60 elements, including genes and pseudogenes and in humans more than 30 elements).[4][20] This means that the genetic information of each individual contains instructions that generate actin variants (called isoforms) that possess slightly different functions. This, in turn, means that eukaryotic organisms express different genes that give rise to: -actin, which is found in contractile structures; -actin, found at the expanding edge of cells that use the projection of their cellular structures as their means of mobility; and -actin, which is found in the filaments of stress fibres.[21] In addition to the similarities that exist between an organisms isoforms there is also an evolutionary conservation in the structure and function even between organisms contained in different eukaryotic domains: in bacteria the actin homologue MreB has been identified, which is a protein that is capable of polymerizing into microfilaments;[4][17] and in archaea the homologue Ta0583 is even more similar to the eukaryotic actins.[22]

Cellular actin has two forms: monomeric globules called G-actin and polymeric filaments called F-actin (that is, as filaments made up of many G-actin monomers). F-actin can also be described as a microfilament. Two parallel F-actin strands must rotate 166 degrees to lie correctly on top of each other. This creates the double helix structure of the microfilaments found in the cytoskeleton. Microfilaments measure approximately 7 nm in diameter with the helix repeating every 37nm. Each molecule of actin is bound to a molecule of adenosine triphosphate (ATP) or adenosine diphosphate (ADP) that is associated with a Mg2+ cation. The most commonly found forms of actin, compared to all the possible combinations, are ATP-G-Actin and ADP-F-actin.[23][24]

Scanning electron microscope images indicate that G-actin has a globular structure; however, X-ray crystallography shows that each of these globules consists of two lobes separated by a cleft. This structure represents the ATPase fold, which is a centre of enzymatic catalysis that binds ATP and Mg2+ and hydrolyzes the former to ADP plus phosphate. This fold is a conserved structural motif that is also found in other proteins that interact with triphosphate nucleotides such as hexokinase (an enzyme used in energy metabolism) or in Hsp70 proteins (a protein family that play an important part in protein folding).[25] G-actin is only functional when it contains either ADP or ATP in its cleft but the form that is bound to ATP predominates in cells when actin is present in its free state.[23]

The X-ray crystallography model of actin that was produced by Kabsch from the striated muscle tissue of rabbits is the most commonly used in structural studies as it was the first to be purified. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 in size, has a molecular mass of 41,785 Da and an estimated isoelectric point of 4.8. Its net charge at pH = 7 is -7.[11][26]

Elzinga and co-workers first determined the complete peptide sequence for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374 amino acid residues. Its N-terminus is highly acidic and starts with an acetyled aspartate in its amino group. While its C-terminus is alkaline and is formed by a phenylalanine preceded by a cysteine, which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous N-methylhistidine is located at position 73.[26]

The tertiary structure is formed by two domains known as the large and the small, which are separated by a cleft centred around the location of the bond with ATP-ADP+Pi. Below this there is a deeper notch called a groove. In the native state, despite their names, both have a comparable depth.[11]

The normal convention in topological studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1-32, 70-144 and 338-374) and subdomain II (upper position, residues 33-69). The larger domain is also divided in two: subdomain III (lower, residues 145-180 and 270-337) and subdomain IV (higher, residues 181-269). The exposed areas of subdomains I and III are referred to as the barbed ends, while the exposed areas of domains II and IV are termed the pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa and IIb, respectively.[27]

The most notable supersecondary structure is a five chain beta sheet that is composed of a -meander and a -- clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication.[12]

The classical description of F-actin states that it has a filamentous structure that can be considered to be a single stranded levorotatory helix with a rotation of 166 around the helical axis and an axial translation of 27.5 , or a single stranded dextrorotatory helix with a cross over spacing of 350-380 , with each actin surrounded by four more.[29] The symmetry of the actin polymer at 2.17 subunits per turn of a helix is incompatible with the formation of crystals, which is only possible with a symmetry of exactly 2, 3, 4 or 6 subunits per turn. Therefore, models have to be constructed that explain these anomalies using data from electron microscopy, cryo-electron microscopy, crystallization of dimers in different positions and diffraction of X-rays.[17][18] It should be pointed out that it is not correct to talk of a structure for a molecule as dynamic as the actin filament. In reality we talk of distinct structural states, in these the measurement of axial translation remains constant at 27.5 while the subunit rotation data shows considerable variability, with displacements of up to 10% from its optimum position commonly seen. Some proteins, such as cofilin appear to increase the angle of turn, but again this could be interpreted as the establishment of different "structural states". These could be important in the polymerization process.[30]

There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a longitude of 25 , current X-ray diffraction data, backed up by cryo-electron microscopy suggests a longitude of 23.7 . These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39-42, 201-203 and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue MreB.[17]

The F-actin polymer is considered to have structural polarity due to the fact that all the microfilaments subunits point towards the same end. This gives rise to a naming convention: the end that possesses an actin subunit that has its ATP binding site exposed is called the "(-) end", while the opposite end where the cleft is directed at a different adjacent monomer is called the "(+) end".[21] The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under transmission electron microscopy when samples are examined following a preparation technique called "decoration". This method consists of the addition of myosin S1 fragments to tissue that has been fixed with tannic acid. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end).[31] A S1 fragment is composed of the head and neck domains of myosin II. Under physiological conditions, G-actin (the monomer form) is transformed to F-actin (the polymer form) by ATP, where the role of ATP is essential.[32]

The helical F-actin filament found in muscles also contains a tropomyosin molecule, which is a 40 nanometre long protein that is wrapped around the F-actin helix.[18] During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the troponins that have three polymers: troponin I, troponin T and troponin C.[33]

Actin can spontaneously acquire a large part of its tertiary structure.[35] However, the way it acquires its fully functional form from its newly synthesized native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the cell cycle.[36][37]

CCT is required in order to ensure that folding takes place correctly. CCT is a group II cytosolic molecular chaperone (or chaperonin, a protein that assists in the folding of other macromolecular structures). CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from other molecular chaperones, particularly from its homologue GroEL which is found in the Archaea, as it does not require a co-chaperone to act as a lid over the central catalytic cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and tubulin, although recent immunoprecipitation studies have shown that it interacts with a large number of polypeptides, which possibly function as substrates. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction.[38]

In order to successfully complete their folding, both actin and tubulin need to interact with another protein called prefoldin, which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have coevolved[citation needed]. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 amino acids long, specifically those at the N-terminal.[39]

Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60-79 and the other between residues 170-198. The actin is recognized, loaded and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldins "tentacles (see the image and note).[35] The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.[34]

The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity.[40] This is why it possesses specific recognition areas in its apical -domain. The first stage in the folding consists of the recognition of residues 245-249. Next, other determinants establish contact.[41] Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actins case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the and -CCT subunits or with -CCT and -CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonins cavity. It also seems that in the case of actin, the CAP protein is required as a possible cofactor in actin's final folding states.[37]

The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to phosducin) inhibits its activity through the formation of a tertiary complex.[38]

Actin is an ATPase, which means that it is an enzyme that hydrolyzes ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is active, that is, its speed increases by some 40,000 times when the actin forms part of a filament.[30] A reference value for this rate of hydrolysis under ideal conditions is around 0.3 s1. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is liberated next to the end of the filament.[42]

The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance.[30] The glutamic acid Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a nucleophilic attack on the ATPs -phosphate bond, while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actins G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPases function would be decoupled straight away.[17][18]

Principal interactions of structural proteins are at cadherin-based adherens junction. Actin filaments are linked to -actinin and to the membrane through vinculin. The head domain of vinculin associates to E-cadherin via -catenin, -catenin, and -catenin. The tail domain of vinculin binds to membrane lipids and to actin filaments.

Actin has been one of the most highly conserved proteins throughout evolution because it interacts with a large number of other proteins. It has 80.2% sequence conservation at the gene level between Homo sapiens and Saccharomyces cerevisiae (a species of yeast), and 95% conservation of the primary structure of the protein product.[4]

Although most yeasts have only a single actin gene, higher eukaryotes, in general, express several isoforms of actin encoded by a family of related genes. Mammals have at least six actin isoforms coded by separate genes,[43] which are divided into three classes (alpha, beta and gamma) according to their isoelectric points. In general, alpha actins are found in muscle (-skeletal, -aortic smooth, -cardiac, and 2-enteric smooth), whereas beta and gamma isoforms are prominent in non-muscle cells (- and 1-cytoplasmic). Although the amino acid sequences and in vitro properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another in vivo.[44]

The typical actin gene has an approximately 100-nucleotide 5' UTR, a 1200-nucleotide translated region, and a 200-nucleotide 3' UTR. The majority of actin genes are interrupted by introns, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution.

All non-spherical prokaryotes appear to possess genes such as MreB, which encode homologues of actin; these genes are required for the cell's shape to be maintained. The plasmid-derived gene ParM encodes an actin-like protein whose polymerized form is dynamically unstable, and appears to partition the plasmid DNA into its daughter cells during cell division by a mechanism analogous to that employed by microtubules in eukaryotic mitosis.[45] Actin is found in both smooth and rough endoplasmic reticulums.

Actin polymerization and depolymerization is necessary in chemotaxis and cytokinesis. Nucleating factors are necessary to stimulate actin polymerization. One such nucleating factor is the Arp2/3 complex, which mimics a G-actin dimer in order to stimulate the nucleation (or formation of the first trimer) of monomeric G-actin. The Arp2/3 complex binds to actin filaments at 70 degrees to form new actin branches off existing actin filaments. Also, actin filaments themselves bind ATP, and hydrolysis of this ATP stimulates destabilization of the polymer.

The growth of actin filaments can be regulated by thymosin and profilin. Thymosin binds to G-actin to buffer the polymerizing process, while profilin binds to G-actin to exchange ADP for ATP, promoting the monomeric addition to the barbed, plus end of F-actin filaments.

F-actin is both strong and dynamic. Unlike other polymers, such as DNA, whose constituent elements are bound together with covalent bonds, the monomers of actin filaments are assembled by weaker bonds. The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the biochemical mechanism by which it is brought about is known as the "assembly dynamic".[6]

Studies focusing on the accumulation and loss of subunits by microfilaments are carried out in vitro (that is, in the laboratory and not on cellular systems) as the polymerization of the resulting actin gives rise to the same F-actin as produced in vivo. The in vivo process is controlled by a multitude of proteins in order to make it responsive to cellular demands, this makes it difficult to observe its basic conditions.[46]

In vitro production takes place in a sequential manner: first, there is the "activation phase", when the bonding and exchange of divalent cations occurs in specific places on the G-actin, which is bound to ATP. This produces a conformational change, sometimes called G*-actin or F-actin monomer as it is very similar to the units that are located on the filament.[27] This prepares it for the "nucleation phase", in which the G-actin gives rise to small unstable fragments of F-actin that are able to polymerize. Unstable dimers and trimers are initially formed. The "elongation phase" begins when there are a sufficiently large number of these short polymers. In this phase the filament forms and rapidly grows through the reversible addition of new monomers at both extremes.[47] Finally, a "stationary equilibrium" is achieved where the G-actin monomers are exchanged at both ends of the microfilament without any change to its total length.[19] In this last phase the "critical concentration Cc" is defined as the ratio between the assembly constant and the dissociation constant for G-actin, where the dynamic for the addition and elimination of dimers and trimers does not produce a change in the microfilament's length. Under normal in vitro conditions Cc is 0.1 M,[48] which means that at higher values polymerization occurs and at lower values depolymerization occurs.[49]

As indicated above, although actin hydrolyzes ATP, everything points to the fact that ATP is not required for actin to be assembled, given that, on one hand, the hydrolysis mainly takes place inside the filament, and on the other hand the ADP could also instigate polymerization. This poses the question of understanding which thermodynamically unfavourable process requires such a prodigious expenditure of energy. The so-called actin cycle, which couples ATP hydrolysis to actin polymerization, consists of the preferential addition of G-actin-ATP monomers to a filaments barbed end, and the simultaneous disassembly of F-actin-ADP monomers at the pointed end where the ADP is subsequently changed into ATP, thereby closing the cycle, this aspect of actin filament formation is known as treadmilling.

ATP is hydrolysed relatively rapidly just after the addition of a G-actin monomer to the filament. There are two hypotheses regarding how this occurs; the stochastic, which suggests that hydrolysis randomly occurs in a manner that is in some way influenced by the neighbouring molecules; and the vectoral, which suggests that hydrolysis only occurs adjacent to other molecules whose ATP has already been hydrolysed. In either case, the resulting Pi is not released, it remains for some time noncovalently bound to actins ADP, in this way there are three species of actin in a filament: ATP-Actin, ADP+Pi-Actin and ADP-Actin.[42][50] The amount of each one of these species present in a filament depends on its length and state: as elongation commences the filament has an approximately equal amount of actin monomers bound with ATP and ADP+Pi and a small amount of ADP-Actin at the (-) end. As the stationary state is reached the situation reverses, with ADP present along the majority of the filament and only the area nearest the (+) end containing ADP+Pi and with ATP only present at the tip.[51]

If we compare the filaments that only contain ADP-Actin with those that include ATP, in the former the critical constants are similar at both ends, while Cc for the other two nucleotides is different: At the (+) end Cc+=0.1 M, while at the (-) end Cc=0.8 M, which gives rise to the following situations:[21]

It is therefore possible to deduce that the energy produced by hydrolysis is used to create a true stationary state, that is a flux, instead of a simple equilibrium, one that is dynamic, polar and attached to the filament. This justifies the expenditure of energy as it promotes essential biological functions.[42] In addition, the configuration of the different monomer types is detected by actin binding proteins, which also control this dynamism, as will be described in the following section.

Microfilament formation by treadmilling has been found to be atypical in stereocilia. In this case the control of the structure's size is totally apical and it is controlled in some way by gene expression, that is, by the total quantity of protein monomer synthesized in any given moment.[52]

The actin cytoskeleton in vivo is not exclusively composed of actin, other proteins are required for its formation, continuance and function. These proteins are called actin-binding proteins (ABP) and they are involved in actins polymerization, depolymerization, stability, organisation in bundles or networks, fragmentation and destruction.[19] The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of protein-protein interactions.[54] For example, G-actin sequestering elements exist that impede its incorporation into microfilaments. There are also proteins that stimulate its polymerization or that give complexity to the synthesizing networks.[21]

Other proteins that bind to actin regulate the length of the microfilaments by cutting them, which gives rise to new active ends for polymerization. For example, if a microfilament with two ends is cut twice, there will be three new microfilaments with six ends. This new situation favors the dynamics of assembly and disassembly. The most notable of these proteins are gelsolin and cofilin. These proteins first achieve a cut by binding to an actin monomer located in the polymer they then change the actin monomers conformation while remaining bound to the newly generated (+) end. This has the effect of impeding the addition or exchange of new G-actin subunits. Depolymerization is encouraged as the (-) ends are not linked to any other molecule.[60]

Other proteins that bind with actin cover the ends of F-actin in order to stabilize them, but they are unable to break them. Examples of this type of protein are CapZ (that binds the (+) ends depending on a cells levels of Ca2+/calmodulin. These levels depend on the cells internal and external signals and are involved in the regulation of its biological functions).[61] Another example is tropomodulin (that binds to the (-) end). Tropomodulin basically acts to stabilize the F-actin present in the myofibrils present in muscle sarcomeres, which are structures characterized by their great stability.[62]

The Arp2/3 complex is widely found in all eukaryotic organisms.[64] It is composed of seven subunits, some of which possess a topology that is clearly related to their biological function: two of the subunits, "ARP2 and "ARP3, have a structure similar to that of actin monomers. This homology allows both units to act as nucleation agents in the polymerization of G-actin and F-actin. This complex is also required in more complicated processes such as in establishing dendritic structures and also in anastomosis (the reconnection of two branching structures that had previously been joined, such as in blood vessels).[65]

There are a number of toxins that interfere with actins dynamics, either by preventing it from polymerizing (latrunculin and cytochalasin D) or by stabilizing it (phalloidin):

Actin forms filaments ('F-actin' or microfilaments) that are essential elements of the eukaryotic cytoskeleton, able to undergo very fast polymerization and depolymerization dynamics. In most cells actin filaments form larger-scale networks which are essential for many key functions in cells:[69]

The actin protein is found in both the cytoplasm and the cell nucleus.[70] Its location is regulated by cell membrane signal transduction pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response. In Dictyostelium, phospholipase D has been found to intervene in inositol phosphate pathways.[71] Actin filaments are particularly stable and abundant in muscle fibres. Within the sarcomere (the basic morphological and physiological unit of muscle fibres) actin is present in both the I and A bands; myosin is also present in the latter.[72]

Microfilaments are involved in the movement of all mobile cells, including non-muscular types, and drugs that disrupt F-actin organization (such as the cytochalasins) affect the activity of these cells. Actin comprises 2% of the total amount of proteins in hepatocytes, 10% in fibroblasts, 15% in amoebas and up to 50-80% in activated platelets.[73] There are a number of different types of actin with slightly different structures and functions. This means that -actin is found exclusively in muscle fibres, while types and are found in other cells. In addition, as the latter types have a high turnover rate the majority of them are found outside permanent structures. This means that the microfilaments found in cells other than muscle cells are present in two forms:[74]

Actins cytoskeleton is key to the processes of endocytosis, cytokinesis, determination of cell polarity and morphogenesis in yeasts. In addition to relying on actin these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cells response to both internal and external stimuli.[76]

Yeasts contain three main elements that are associated with actin: patches, cables and rings that, despite being present for long, are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called COF1; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to adenylate cyclase proteins; a profilin with a molecular weight of approximately 14 kDa that is associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches.[76]

Plant genome studies have revealed the existence of protein isovariants within the actin family of genes. Within Arabidopsis thaliana, a dicotyledon used as a model organism, there are ten types of actin, nine types of -tubulins, six -tubulins, six profilins and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression.[4] The majority of these proteins were jointly expressed in the tissue analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated in vitro. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization.[77]

Even though the majority of plant cells have a cell wall that defines their morphology and impedes their movement, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as, the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve cell division as well as the elongation and differentiation of the cell.[79]

The most notable proteins associated with the actin cytoskeleton in plants include:[79]villin, which belongs to the same family as gelsolin/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; fimbrin, which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts);[80]formins, which are able to act as an F-actin polymerization nucleating agent; myosin, a typical molecular motor that is specific to eukaryotes and which in Arabidopsis thaliana is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of chloroplasts in the cell; KAM1/MUR3 that define the morphology of the Golgi apparatus as well as the composition of xyloglucans in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within membranes and microfilaments and which seems to play a role that is involved in an organisms reaction to stress.

Nuclear actin was first noticed and described in 1977 by Clark and Merriam.[81] Authors describe a protein present in the nuclear fraction, obtained from Xenopus laevis oocytes, which shows the same features such skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.[82]) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.

The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion.[83] Actin however shuttles between cytoplasm and nucleus quite quickly, which indicates the existence of active transport. The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9.[84]

Low level of actin in the nucleus seems to be very important, because actin has two nuclear export signals (NES) into its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through exportin 1 (EXP1) and exportin 6 (Exp6).[85][86]

Specific modifications, such as SUMOylation, allows for nuclear actin retention. It was demonstrated that a mutation preventing SUMOylation causes rapid export of beta actin from the nucleus.[87]

Based on the experimental results a general mechanism of nuclear actin transport can be proposed:[87][88]

Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers.[89][90][91] Nuclear actin organization varies in different cell types. For example, in Xenopus oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining.[81][83]

In somatic cell nucleus however we cannot observe any actin filaments using this technique.[92] The DNase I inhibition assay, so far the only test which allows the quantification of the polymerized actin directly in biological samples, have revealed that endogenous nuclear actin occurs indeed mainly in a monomeric form.[91]

Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.[88]

Little attention is paid to actin isoforms, however it has been shown that different isoforms of actin are present in the cell nucleus. Actin isoforms, despite of their high sequence similarity, have different biochemical properties such as polymerization and depolymerization kinetic.[93] They also shows different localization and functions.

The level of actin isoforms, both in the cytoplasm and the nucleus, may change for example in response to stimulation of cell growth or arrest of proliferation and transcriptional activity.[94]

Research concerns on nuclear actin are usually focused on isoform beta.[95][96][97][98] However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also:

The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, especially because the level of individual isoforms can be controlled independently.[91]

Functions of actin in the nucleus are associated with its ability to polymerization, interaction with variety of ABPs and with structural elements of the nucleus. Nuclear actin is involved in:

Due to its ability to conformational changes and interaction with many proteins actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex.[105]

In muscle cells, actomyosin myofibrils makeup much of the cytoplasmic material. These myofibrils are made of thin filaments of actin (typically around 7nm in diameter), and thick filaments of the motor-protein myosin (typically around 15nm in diameter).[121] These myofibrils use energy derived from ATP to create movements of cells, such as muscle contraction.[121] Using the hydrolysis of ATP for energy, myosin heads undergo a cycle during which they attach to thin filaments, exert a tension, and then, depending on the load, perform a power stroke that causes the thin filaments to slide past, shortening the muscle.

In contractile bundles, the actin-bundling protein alpha-actinin separates each thin filament by ~35nm. This increase in distance allows thick filaments to fit in between and interact, enabling deformation or contraction. In deformation, one end of myosin is bound to the plasma membrane, while the other end "walks" toward the plus end of the actin filament. This pulls the membrane into a different shape relative to the cell cortex. For contraction, the myosin molecule is usually bound to two separate filaments and both ends simultaneously "walk" toward their filament's plus end, sliding the actin filaments closer to each other. This results in the shortening, or contraction, of the actin bundle (but not the filament). This mechanism is responsible for muscle contraction and cytokinesis, the division of one cell into two.

The helical F-actin filament found in muscles also contains a tropomyosin molecule, a 40-nanometre protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction (the interaction gives rise to a movement between the two proteins that, because it is repeated many times, produces a contraction). There are other protein molecules bound to the tropomyosin thread, these include the troponins that have three polymers: troponin I, troponin T, and troponin C.[33] Tropomyosins regulatory function depends on its interaction with troponin in the presence of Ca2+ ions.[122]

Both actin and myosin are involved in muscle contraction and relaxation and they make up 90% of muscle protein.[123] The overall process is initiated by an external signal, typically through an action potential stimulating the muscle, which contains specialized cells whose interiors are rich in actin and myosin filaments. The contraction-relaxation cycle comprises the following steps:[72]

The traditional image of actins function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cells shape.[74] However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in prokaryotes.

The majority of mammals possess six different actin genes. Of these, two code for the cytoskeleton (ACTB and ACTG1) while the other four are involved in skeletal striated muscle (ACTA1), smooth muscle tissue (ACTA2), intestinal muscles (ACTG2) and cardiac muscle (ACTC1). The actin in the cytoskeleton is involved in the pathogenic mechanisms of many infectious agents, including HIV. The vast majority of the mutations that affect actin are point mutations that have a dominant effect, with the exception of six mutations involved in nemaline myopathy. This is because in many cases the mutant of the actin monomer acts as a cap by preventing the elongation of F-actin.[27]

ACTA1 is the gene that codes for the -isoform of actin that is predominant in human skeletal striated muscles, although it is also expressed in heart muscle and in the thyroid gland.[141] Its DNA sequence consists of seven exons that produce five known transcripts.[142] The majority of these consist of point mutations causing substitution of amino acids. The mutations are in many cases associated with a phenotype that determines the severity and the course of the affliction.[27][142]

The mutation alters the structure and function of skeletal muscles producing one of three forms of myopathy: type 3 nemaline myopathy, congenital myopathy with an excess of thin myofilaments (CM) and Congenital myopathy with fibre type disproportion (CMFTD). Mutations have also been found that produce core myopathies).[144] Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these phenotypes in a biopsy.[145] The most common symptoms consist of a typical facial morphology (myopathic faces), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemalinic myopathy is that Nemaline rods appear in differing places in Type 1 muscle fibres. These rods are non-pathognomonic structures that have a similar composition to the Z disks found in the sarcomere.[146]

The pathogenesis of this myopathy is very varied. Many mutations occur in the region of actins indentation near to its nucleotide binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies.[27] Changes in actins folding occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the expression of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the nucleuss protein exportation signal so that the accumulation of actin's mutated form occurs in the cell nucleus.[147] On the other hand, it appears that mutations to ACTA1 that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure.[148] Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater apoptosis rate in type II muscular fibres.[36]

There are two isoforms that code for actins in the smooth muscle tissue:

ACTG2 codes for the largest actin isoform, which has nine exons, one of which, the one located at the 5' end, is not translated.[149] It is an -actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although microarrays have shown that this protein is more often expressed in cases that are resistant to chemotherapy using cisplatin.[150]

ACTA2 codes for an -actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary thoracic aortic aneurisms particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the aortic media has been recorded in these individuals, with areas of disorganization and hyperplasia as well as stenosis of the aortas vasa vasorum.[151] The number of afflictions that the gene is implicated in is increasing. It has been related to Moyamoya disease and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and ischaemic heart disease.[152] The -actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.[153]

The ACTC1 gene codes for the -actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns.[154] It was the first of the six genes where alleles were found that were implicated in pathological processes.[155]

A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R dilated cardiomyopathy and Type 11 hypertrophic cardiomyopathy. Certain defects of the atrial septum have been described recently that could also be related to these mutations.[157][158]

Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved amino acids belonging to the protein domains that bind and intersperse with the Z discs. This has led to the theory that the dilation is produced by a defect in the transmission of contractile force in the myocytes.[29][155]

The mutations inACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies.[159] The existence of a number of point mutations have also been found:[160]

Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the hearts ability to contract causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscles normal response to stress.[161]

Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy,[162] and noncompaction of the left ventricular myocardium.[163]

ACTB is a highly complex locus. A number of pseudogenes exist that are distributed throughout the genome, and its sequence contains six exons that can give rise to up to 21 different transcriptions by alternative splicing, which are known as the -actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes (cytoskeleton, NuA4 histone-acyltransferase complex, cell nucleus) and in addition they are associated with the mechanisms of a great number of pathological processes (carcinomas, juvenile dystonia, infection mechanisms, nervous system malformations and tumour invasion, among others).[164] A new form of actin has been discovered, kappa actin, which appears to substitute for -actin in processes relating to tumours.[165]

Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence:

The ACTG1 locus codes for the cytosolic -actin protein that is responsible for the formation of cytoskeletal microfilaments. It contains six exons, giving rise to 22 different mRNAs, which produce four complete isoforms whose form of expression is probably dependent on the type of tissue they are found in. It also has two different DNA promoters.[170] It has been noted that the sequences translated from this locus and from that of -actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion.[171]

In terms of pathology, it has been associated with processes such as amyloidosis, retinitis pigmentosa, infection mechanisms, kidney diseases and various types of congenital hearing loss.[170]

Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the stereocilia of the ciliated cells present in the inner ears Organ of Corti. -actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin.[27] Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal.[172]

However, although there is no record of any case, it is known that -actin is also expressed in skeletal muscles, and although it is present in small quantities, model organisms have shown that its absence can give rise to myopathies.[173]

Some infectious agents use actin, especially cytoplasmic actin, in their life cycle. Two basic forms are present in bacteria:

In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably HIV, by, for example, inactivating the cofilin complex.[178]

The role that actin plays in the invasion process of cancer cells has still not been determined.[179]

The eukaryotic cytoskeleton of organisms among all taxonomic groups have similar components to actin and tubulin. For example, the protein that is coded by the ACTG2 gene in humans is completely equivalent to the homologues present in rats and mice, even though at a nucleotide level the similarity decreases to 92%.[149] However, there are major differences with the equivalents in prokaryotes (FtsZ and MreB), where the similarity between nucleotide sequences is between 4050% among different bacteria and archaea species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons.[4][180]

Some authors point out that the behaviour of actin, tubulin and histone, a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of Brownian motion. It has also been suggested that they all have a common ancestor.[181] Therefore, evolutionary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as endocytosis.[182]

Continued here:
Actin - Wikipedia

This article is about skin in humans. For other animals, see skin.

The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs.[1] Human skin is similar to that of most other mammals. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin.[2] The adjective cutaneous literally means "of the skin" (from Latin cutis, skin).

Because it interfaces with the environment, skin plays an important immunity role in protecting the body against pathogens[3] and excessive water loss.[4] Its other functions are insulation, temperature regulation, sensation, synthesis of vitamin D, and the protection of vitamin B folates. Severely damaged skin will try to heal by forming scar tissue. This is often discolored and depigmented.

In humans, skin pigmentation varies among populations, and skin type can range from dry to oily. Such skin variety provides a rich and diverse habitat for bacteria that number roughly 1000 species from 19 phyla, present on the human skin.[5][6]

Skin has mesodermal cells, pigmentation, such as melanin provided by melanocytes, which absorb some of the potentially dangerous ultraviolet radiation (UV) in sunlight. It also contains DNA repair enzymes that help reverse UV damage, such that people lacking the genes for these enzymes suffer high rates of skin cancer. One form predominantly produced by UV light, malignant melanoma, is particularly invasive, causing it to spread quickly, and can often be deadly. Human skin pigmentation varies among populations in a striking manner. This has led to the classification of people(s) on the basis of skin color.[7]

The skin is the largest organ in the human body. For the average adult human, the skin has a surface area of between 1.5-2.0 square metres (16.1-21.5 sq ft.). The thickness of the skin varies considerably over all parts of the body, and between men and women and the young and the old. An example is the skin on the forearm which is on average 1.3mm in the male and 1.26mm in the female.[8] The average square inch (6.5cm) of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than 1,000 nerve endings.[9][bettersourceneeded] The average human skin cell is about 30 micrometers in diameter, but there are variants. A skin cell usually ranges from 25-40 micrometers (squared), depending on a variety of factors.

Skin is composed of three primary layers: the epidermis, the dermis and the hypodermis.[8]

Epidermis, "epi" coming from the Greek meaning "over" or "upon", is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface which also serves as a barrier to infection and is made up of stratified squamous epithelium with an underlying basal lamina.

The epidermis contains no blood vessels, and cells in the deepest layers are nourished almost exclusively by diffused oxygen from the surrounding air[10] and to a far lesser degree by blood capillaries extending to the outer layers of the dermis. The main type of cells which make up the epidermis are Merkel cells, keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basale layer. The daughter cells (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source. The cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called "keratinization". This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection.

The epidermis contains no blood vessels, and is nourished by diffusion from the dermis. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. The epidermis helps the skin to regulate body temperature.

Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and are sloughed off, or desquamated. This process is called keratinization and takes place within weeks. The outermost layer of the epidermis consists of 25 to 30 layers of dead cells.

Epidermis is divided into the following 5 sublayers or strata:

Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. Arterial shunt vessels may bypass the network in ears, the nose and fingertips.

The dermis is the layer of skin beneath the epidermis that consists of epithelial tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as from the Stratum basale of the epidermis.

The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region.

The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin.

In the palms, fingers, soles, and toes, the influence of the papillae projecting into the epidermis forms contours in the skin's surface. These epidermal ridges occur in patterns (see: fingerprint) that are genetically and epigenetically determined and are therefore unique to the individual, making it possible to use fingerprints or footprints as a means of identification.

The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity.

Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels.

Tattoo ink is held in the dermis. Stretch marks from pregnancy are also located in the dermis.

The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue, adipose tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body.

Human skin shows high skin color variety from the darkest brown to the lightest pinkish-white hues. Human skin shows higher variation in color than any other single mammalian species and is the result of natural selection. Skin pigmentation in humans evolved to primarily regulate the amount of ultraviolet radiation (UVR) penetrating the skin, controlling its biochemical effects.[11]

The actual skin color of different humans is affected by many substances, although the single most important substance determining human skin color is the pigment melanin. Melanin is produced within the skin in cells called melanocytes and it is the main determinant of the skin color of darker-skinned humans. The skin color of people with light skin is determined mainly by the bluish-white connective tissue under the dermis and by the hemoglobin circulating in the veins of the dermis. The red color underlying the skin becomes more visible, especially in the face, when, as consequence of physical exercise or the stimulation of the nervous system (anger, fear), arterioles dilate.[12]

There are at least five different pigments that determine the color of the skin.[13][14] These pigments are present at different levels and places.

There is a correlation between the geographic distribution of UV radiation (UVR) and the distribution of indigenous skin pigmentation around the world. Areas that highlight higher amounts of UVR reflect darker-skinned populations, generally located nearer towards the equator. Areas that are far from the tropics and closer to the poles have lower concentration of UVR, which is reflected in lighter-skinned populations.[15]

In the same population it has been observed that adult human females are considerably lighter in skin pigmentation than males. Females need more calcium during pregnancy and lactation and vitamin D which is synthesized from sunlight helps in absorbing calcium. For this reason it is thought that females may have evolved to have lighter skin in order to help their bodies absorb more calcium.[16]

The Fitzpatrick scale[17][18] is a numerical classification schema for human skin color developed in 1975 as a way to classify the typical response of different types of skin to ultraviolet (UV) light:

As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself as a person ages.

Among other things, skin aging is noted by a decrease in volume and elasticity. There are many internal and external causes to skin aging. For example, aging skin receives less blood flow and lower glandular activity.

A validated comprehensive grading scale has categorized the clinical findings of skin aging as laxity (sagging), rhytids (wrinkles), and the various facets of photoaging, including erythema (redness), and telangiectasia, dyspigmentation (brown discoloration), solar elastosis (yellowing), keratoses (abnormal growths) and poor texture.[19]

Cortisol causes degradation of collagen,[20] accelerating skin aging.[21]

Anti-aging supplements are used to treat skin aging.

Photoaging has two main concerns: an increased risk for skin cancer and the appearance of damaged skin. In younger skin, sun damage will heal faster since the cells in the epidermis have a faster turnover rate, while in the older population the skin becomes thinner and the epidermis turnover rate for cell repair is lower which may result in the dermis layer being damaged.[22]

Skin performs the following functions:

The human skin is a rich environment for microbes.[5][6] Around 1000 species of bacteria from 19 bacterial phyla have been found. Most come from only four phyla: Actinobacteria (51.8%), Firmicutes (24.4%), Proteobacteria (16.5%), and Bacteroidetes (6.3%). Propionibacteria and Staphylococci species were the main species in sebaceous areas. There are three main ecological areas: moist, dry and sebaceous. In moist places on the body Corynebacteria together with Staphylococci dominate. In dry areas, there is a mixture of species but dominated by b-Proteobacteria and Flavobacteriales. Ecologically, sebaceous areas had greater species richness than moist and dry ones. The areas with least similarity between people in species were the spaces between fingers, the spaces between toes, axillae, and umbilical cord stump. Most similarly were beside the nostril, nares (inside the nostril), and on the back.

Reflecting upon the diversity of the human skin researchers on the human skin microbiome have observed: "hairy, moist underarms lie a short distance from smooth dry forearms, but these two niches are likely as ecologically dissimilar as rainforests are to deserts."[5]

The NIH has launched the Human Microbiome Project to characterize the human microbiota which includes that on the skin and the role of this microbiome in health and disease.[23]

Microorganisms like Staphylococcus epidermidis colonize the skin surface. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

Diseases of the skin include skin infections and skin neoplasms (including skin cancer).

Dermatology is the branch of medicine that deals with conditions of the skin.[2]

The skin supports its own ecosystems of microorganisms, including yeasts and bacteria, which cannot be removed by any amount of cleaning. Estimates place the number of individual bacteria on the surface of one square inch (6.5 square cm) of human skin at 50 million, though this figure varies greatly over the average 20 square feet (1.9m2) of human skin. Oily surfaces, such as the face, may contain over 500 million bacteria per square inch (6.5cm). Despite these vast quantities, all of the bacteria found on the skin's surface would fit into a volume the size of a pea.[24] In general, the microorganisms keep one another in check and are part of a healthy skin. When the balance is disturbed, there may be an overgrowth and infection, such as when antibiotics kill microbes, resulting in an overgrowth of yeast. The skin is continuous with the inner epithelial lining of the body at the orifices, each of which supports its own complement of microbes.

Cosmetics should be used carefully on the skin because these may cause allergic reactions. Each season requires suitable clothing in order to facilitate the evaporation of the sweat. Sunlight, water and air play an important role in keeping the skin healthy.

Oily skin is caused by over-active sebaceous glands, that produce a substance called sebum, a naturally healthy skin lubricant.[1] When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples.[1] The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging,[1] because the oil helps to keep needed moisture locked into the epidermis (outermost layer of skin).

The negative aspect of the oily-skin type is that oily complexions are especially susceptible to clogged pores, blackheads, and buildup of dead skin cells on the surface of the skin.[1] Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck.[1]

Human skin has a low permeability; that is, most foreign substances are unable to penetrate and diffuse through the skin. Skin's outermost layer, the stratum corneum, is an effective barrier to most inorganic nanosized particles.[25][26] This protects the body from external particles such as toxins by not allowing them to come into contact with internal tissues. However, in some cases it is desirable to allow particles entry to the body through the skin. Potential medical applications of such particle transfer has prompted developments in nanomedicine and biology to increase skin permeability. One application of transcutaneous particle delivery could be to locate and treat cancer. Nanomedical researchers seek to target the epidermis and other layers of active cell division where nanoparticles can interact directly with cells that have lost their growth-control mechanisms (cancer cells). Such direct interaction could be used to more accurately diagnose properties of specific tumors or to treat them by delivering drugs with cellular specificity.

Nanoparticles 40nm in diameter and smaller have been successful in penetrating the skin.[27][28][29] Research confirms that nanoparticles larger than 40nm do not penetrate the skin past the stratum corneum.[27] Most particles that do penetrate will diffuse through skin cells, but some will travel down hair follicles and reach the dermis layer.

The permeability of skin relative to different shapes of nanoparticles has also been studied. Research has shown that spherical particles have a better ability to penetrate the skin compared to oblong (ellipsoidal) particles because spheres are symmetric in all three spatial dimensions.[29] One study compared the two shapes and recorded data that showed spherical particles located deep in the epidermis and dermis whereas ellipsoidal particles were mainly found in the stratum corneum and epidermal layers.[30]Nanorods are used in experiments because of their unique fluorescent properties but have shown mediocre penetration.

Nanoparticles of different materials have shown skins permeability limitations. In many experiments, gold nanoparticles 40nm in diameter or smaller are used and have shown to penetrate to the epidermis. Titanium oxide (TiO2), zinc oxide (ZnO), and silver nanoparticles are ineffective in penetrating the skin past the stratum corneum.[31][32]Cadmium selenide (CdSe) quantum dots have proven to penetrate very effectively when they have certain properties. Because CdSe is toxic to living organisms, the particle must be covered in a surface group. An experiment comparing the permeability of quantum dots coated in polyethylene glycol (PEG), PEG-amine, and carboxylic acid concluded the PEG and PEG-amine surface groups allowed for the greatest penetration of particles. The carboxylic acid coated particles did not penetrate past the stratum corneum.[30]

Scientists previously believed that the skin was an effective barrier to inorganic particles. Damage from mechanical stressors was believed to be the only way to increase its permeability.[33] Recently, however, simpler and more effective methods for increasing skin permeability have been developed. For example, ultraviolet radiation (UVR) has been used to slightly damage the surface of skin, causing a time-dependent defect allowing easier penetration of nanoparticles.[34] The UVRs high energy causes a restructuring of cells, weakening the boundary between the stratum corneum and the epidermal layer.[34][35] The damage of the skin is typically measured by the transepidermal water loss (TEWL), though it may take 35 days for the TEWL to reach its peak value. When the TEWL reaches its highest value, the maximum density of nanoparticles is able to permeate the skin. Studies confirm that UVR damaged skin significantly increases the permeability.[34][35] The effects of increased permeability after UVR exposure can lead to an increase in the number of particles that permeate the skin. However, the specific permeability of skin after UVR exposure relative to particles of different sizes and materials has not been determined.[34]

Other skin damaging methods used to increase nanoparticle penetration include tape stripping, skin abrasion, and chemical enhancement. Tape stripping is the process in which tape is applied to skin then lifted to remove the top layer of skin. Skin abrasion is done by shaving the top 5-10 micrometers off the surface of the skin. Chemical enhancement is the process in which chemicals such as polyvinylpyrrolidone (PVP), dimethyl sulfoxide (DMSO), and oleic acid are applied to the surface of the skin to increase permeability.[36][37]

Electroporation is the application of short pulses of electric fields on skin and has proven to increase skin permeability. The pulses are high voltage and on the order of milliseconds when applied. Charged molecules penetrate the skin more frequently than neutral molecules after the skin has been exposed to electric field pulses. Results have shown molecules on the order of 100 micrometers to easily permeate electroporated skin.[37]

A large area of interest in nanomedicine is the transdermal patch because of the possibility of a painless application of therapeutic agents with very few side effects. Transdermal patches have been limited to administer a small number of drugs, such as nicotine, because of the limitations in permeability of the skin. Development of techniques that increase skin permeability has led to more drugs that can be applied via transdermal patches and more options for patients.[37]

Increasing the permeability of skin allows nanoparticles to penetrate and target cancer cells. Nanoparticles along with multi-modal imaging techniques have been used as a way to diagnose cancer non-invasively. Skin with high permeability allowed quantum dots with an antibody attached to the surface for active targeting to successfully penetrate and identify cancerous tumors in mice. Tumor targeting is beneficial because the particles can be excited using fluorescence microscopy and emit light energy and heat that will destroy cancer cells.[38]

Sunblock and sunscreen are different important skin-care products though both offer full protection from the sun.[39][40]

SunblockSunblock is opaque and stronger than sunscreen, since it is able to block most of the UVA/UVB rays and radiation from the sun, and does not need to be reapplied several times in a day. Titanium dioxide and zinc oxide are two of the important ingredients in sunblock.[41]

SunscreenSunscreen is more transparent once applied to the skin and also has the ability to protect against UVA/UVB rays, although the sunscreen's ingredients have the ability to break down at a faster rate once exposed to sunlight, and some of the radiation is able to penetrate to the skin. In order for sunscreen to be more effective it is necessary to consistently reapply and use one with a higher sun protection factor.

Vitamin A, also known as retinoids, benefits the skin by normalizing keratinization, downregulating sebum production which contributes to acne, and reversing and treating photodamage, striae, and cellulite.

Vitamin D and analogs are used to downregulate the cutaneous immune system and epithelial proliferation while promoting differentiation.

Vitamin C is an antioxidant that regulates collagen synthesis, forms barrier lipids, regenerates vitamin E, and provides photoprotection.

Vitamin E is a membrane antioxidant that protects against oxidative damage and also provides protection against harmful UV rays. [42]

Several scientific studies confirmed that changes in baseline nutritional status affects skin condition. [43]

The Mayo Clinic lists foods they state help the skin: yellow, green, and orange fruits and vegetables; fat-free dairy products; whole-grain foods; fatty fish, nuts.[44]

Read more:
Human skin - Wikipedia

In August, 2011 an all natural rejuvenating serum that uses your own adult stem cells to decrease wrinkles and increase moisture retention and elasticity was launched in the United States, and subsequently in Australia. This is a mocha based fusion of the world's most restorative ingredients and a blend of six cytokines that stimulate the proliferation and migration of the skin's stem cells by more than 225%.

There are a number of stem cell based serums and skin care products that have appeared on the marketplace over the past few years, and they constitute a novel frontier in skin care. Although many of them are nothing more than simple skin care products with misleading or spurious stem cell claims, a few are legitimate products. The legitimate ones are all based on the use of compounds called cytokines, which are growth factors supporting the functions of stem cells in the skin. Some of them contain an extract from apple stem cells, whose effectiveness really remains to be proven there is an obvious difference between human skin and an apple! Others contained cytokines from human stem cells. The latter are obviously the premium products.

One of the questions the developers of this product asked was: Of all the natural compounds and herbal extracts known to benefit the skin, which do so by supporting the natural role of stem cells in the skin? Are there natural compounds that can support the intrinsic ability of the skin to renew itself? They studied a broad array of plants and herbal extracts for their effect on the proliferation and differentiation of human skin stem cells grown in vitro, and they discovered a handful of natural compounds that have an effect on the very stem cells of your skin. By supporting the natural role of your skins stem cells, you support the process of rejuvenation of your skin from within.......the way nature intended. These compounds include AFA, the same product from which stem cell nutrition is derived.

AFA alone increased the proliferation of skin stem cells by nearly 100% in the study. Other natural ingredients include: Aloe vera (which increased skin stem cell proliferation by 87%) and a proprietary fucoidan that increased proliferation by 55%. When blended together, the effect of these plants on skin stem cell proliferation was further synergistically increased by ingredients like vanilla, maqui berry, cacao, old mans weed and others. All these ingredients taken together constitute the Stem Cell Complex unique to this product with a Stem Cell Index exceeding 250%

Hyaluronic acid is part of the infrastructure (skeleton of the skin) and is one of the main components forming the matrix of the skin. One of the main roles of hyaluronic acid is to retain moisture in the skin. Good hydration is the hallmark of young skin, and it comes from the presence of hyaluronic acid. Recently a group of scientists discovered that as we age, although we continue to produce hyaluronic acid, its structure is less and less branched. The highly branched hyaluronic acid in young skin allows for greater retention of water in the skin. Since these branches are formed of a derivative of glucosamine, scientists discovered that the best results are obtained when this derivative of glucosamine is applied on the skin, instead of hyaluronic acid itself. This product is the first in the US to contain that very derivative of glucosamine, produced by fermentation.

An all-natural formula Of all the stem cell based skin care products, this is the only one that is truly natural ......even though many make the claim. In essence, all skin care products are oils blended with water extracts of various plants. Since oil and water do not mix, it is necessary to use compounds called emulsifiers that can dissolve in both water and in lipids, thereby helping to create an emulsion. There are very few natural emulsifiers and none that are known to be effective at making a cold emulsion which is essential to the preservation of all the delicate actives found in herbal extracts. This is the only skin care product made cold with an all-natural emulsification system. Products like glycerin are relatively natural and can be used as emulsifiers; however, they are known for their drying effect on the skin. There is no glycerin here. Once produced, natural skin care products are essentially food for bacteria, so they need to be preserved. And this is the biggest challenge, as there are virtually no natural preservatives commercially available. Although the best products claim to have none of the dangerous carcinogenic parabens, they have other compounds just as dangerous such as phenoxyethanol and various forms of benzoic acid, all known to be irritants to the skin. The developers asked the question, Where in nature can we find natural antibacterial compounds? They harvested several flowers known to grow in very moist areas while blooming for weeks, unaffected by bacterial or fungal growth, and they extracted their antibacterial power. To this they added a proprietary process called SoniPure that inactivates bacteria by the use of sound waves a breakthrough innovative process. So this skin serum is 100% stable without delivering harmful compounds to your skin.

The developers intention was to create a product to restructure the skin from within in order to increase water retention and skin elasticity, which in turn would naturally reduce wrinkles and fine lines and this is exactly what was demonstrated in an independent clinical trial. It was shown to increase water retention by 30% and skin elasticity by 10% and to reduce wrinkles by an average of 25% in 28 days. Some people saw significant benefits after only 7 days, while others report wrinkle reduction by as much as 75%. In all participants, wrinkle reduction was already statistically significant after 7 days. So you can easily see how both the developmental process and the resulting formula ensure that this product is undeniably second-to-none in stem cell based skin care.

In healthy individuals, skin youthfulness is maintained by epidermal stem cells which self-renew and generate daughter cells that become new skin. Therefore, part of skin aging is caused by impaired adult stem cell mobilization from the bone marrow and the reduced number of adult stem cells able to respond to repair signals. This means that, if we increase the number of circulating adult stem cells, we can affect the epidermal stem cells. Research also shows that topical application of cytokines stimulates the migration and proliferation of skin stem cells.

In much the same way as stem cell nutrition works with adult stem cells to deliver inner wellness, the rejuvenating skin serum applies the benefits of adult stem cell science to the bodys largest organ, the skin, to achieve and maintain outer vibrance! Taking care of this organ the skin, which exposed to the elements on a continual basis is essential. The rejuvenating skin serum assists in our daily process at the skin level, by a proprietary blend of over two dozen natural ingredients found during years of searching worldwide. Each natural ingredient has been selected for its nutrient-rich attributes that fight the appearance of aging, regenerating cells, decreasing fine lines and wrinkles, increasing moisture retention and increasing skin elasticity. In addition, some of the ingredients have natural sun-protecting components.

After using stem cell serum on one side of face only for only 10 days

Your skin's response to an increase in circulating adult stem cells. The most evident visual response in people's facial skin a few weeks after taking stem cell nutrition is that - it glows. People notice a smoothness and improvement in color of their skin. Skin may also show improvements in age related and hormonal pigmentation, decreased bruising and increased elasticity and tone.

Before and after using stem cell serum

This product is second to none, and early clinical tests have demonstrated the following dramatic results: Decreased fine line & coarse wrinkles 25% in 28 days Increased moisture retention 30% in 28 days Increased elasticity 10% in 28 days

See original here:
Rejuvenating Skin Serum - Stem Cell Nutrition

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Guidelines for Preventing Opportunistic Infections Among ...

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Article

The Arabidopsis CERK1associated kinase PBL27 connects chitin perception to MAPK activation

These authors contributed equally to this work as first authors

These authors contributed equally to this work as third authors

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

CERK1associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.

Chitin perception induces disassociation of PBL27 and MAPKKK5.

PBL27 functions as a MAPKKK kinase.

Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.

Phosphorylation of MAPKKK5 by PBL27 is required for chitininduced MAPK activation in planta.

Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki

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Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

Continued here:
Cell Size and Scale - Learn Genetics

Do you ever wonder what makes up blood? Unless you need to have blood drawn, donate it or have to stop its flow after an injury, you probably don't think much about it. But blood is the most commonly tested part of the body, and it is truly the river of life. Every cell in the body gets its nutrients from blood. Understanding blood will help you as your doctor explains the results of your blood tests. In addition, you will learn amazing things about this incredible fluid and the cells in it.

Blood is a mixture of two components: cells and plasma. The heart pumps blood through the arteries, capillaries and veins to provide oxygen and nutrients to every cell of the body. The blood also carries away waste products.

The adult human body contains approximately 5 liters (5.3 quarts) of blood; it makes up 7 to 8 percent of a person's body weight. Approximately 2.75 to 3 liters of blood is plasma and the rest is the cellular portion.

Plasma is the liquid portion of the blood. Blood cells like red blood cells float in the plasma. Also dissolved in plasma are electrolytes, nutrients and vitamins (absorbed from the intestines or produced by the body), hormones, clotting factors, and proteins such as albumin and immunoglobulins (antibodies to fight infection). Plasma distributes the substances it contains as it circulates throughout the body.

The cellular portion of blood contains red blood cells (RBCs), white blood cells (WBCs) and platelets. The RBCs carry oxygen from the lungs; the WBCs help to fight infection; and platelets are parts of cells that the body uses for clotting. All blood cells are produced in the bone marrow. As children, most of our bones produce blood. As we age this gradually diminishes to just the bones of the spine (vertebrae), breastbone (sternum), ribs, pelvis and small parts of the upper arm and leg. Bone marrow that actively produces blood cells is called red marrow, and bone marrow that no longer produces blood cells is called yellow marrow. The process by which the body produces blood is called hematopoiesis. All blood cells (RBCs, WBCs and platelets) come from the same type of cell, called the pluripotential hematopoietic stem cell. This group of cells has the potential to form any of the different types of blood cells and also to reproduce itself. This cell then forms committed stem cells that will form specific types of blood cells.

We'll learn more about red blood cells in detail next.

Originally posted here:
How Blood Works | HowStuffWorks

An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche"). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or "repopulate") their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

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Stem Cell Basics IV. | stemcells.nih.gov

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NIH Osteoporosis and Related Bone Diseases ~ National Resource Center

Researchers employ an emerging approach used to fight cancer and turn it on pemphigus. They engineer T cells to destroy misbehaving immune cells without affecting the rest of the immune system.

Read more about engineering a T cell.

Investigators have discovered that a molecule called TRPV4 plays a role in sensing itch. The discovery may lead to new ways to treat skin conditions.

Find out more about TRPV4.

Psoriasis is a chronic skin disease that causes scaling and inflammation. It's driven by the immune system. Research is helping to find improved treatments.

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Using a combination of medicinal chemistry and biomaterials science, researchers have engineered a way to attract immune cells to a site of injury in mice and stimulate the formation of new blood vessels.

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On behalf of the organizing committee, it is my distinct pleasure to invite you to attend the Stem Cell Congress-2017. After the success of the Cell Science-2011, 2012, 2013, 2014, 2015, Conference series.LLC is proud to announce the 6th World Congress and expo on Cell & Stem Cell Research (Stem Cell Congress-2017) which is going to be held during March 20-22, 2017, Orlando, Florida, USA. The theme of Stem Cell Congress-2017 is Explore and Exploit the Novel Techniques in Cell and Stem Cell Research.

This annual Cell Science conference brings together domain experts, researchers, clinicians, industry representatives, postdoctoral fellows and students from around the world, providing them with the opportunity to report, share, and discuss scientific questions, achievements, and challenges in the field.

Examples of the diverse cell science and stem cell topics that will be covered in this comprehensive conference include Cell differentiation and development, Cell metabolism, Tissue engineering and regenerative medicine, Stem cell therapy, Cell and gene therapy, Novel stem cell technologies, Stem cell and cancer biology, Stem cell treatment, Tendency in cell biology of aging and Apoptosis and cancer disease, Drugs and clinical developments. The meeting will focus on basic cell mechanism studies, clinical research advances, and recent breakthroughs in cell and stem cell research. With the support of many emerging technologies, dramatic progress has been made in these areas. In Stem Cell Congress-2017, you will be able to share experiences and research results, discuss challenges encountered and solutions adopted and have opportunities to establish productive new academic and industry research collaborations.

In association with the Stem Cell Congress-2017 conference, we will invite those selected to present at the meeting to publish a manuscript from their talk in the journal Cell Science with a significantly discounted publication charge. Please join us in Philadelphia for an exciting all-encompassing annual Stem Cell get together with the theme of better understanding from basic cell mechanisms to latest Stem Cell breakthroughs!

Haval Shirwan, Ph.D. Executive Editor, Journal of Clinical & Cellular Immunology Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease Professor, Department of Microbiology and Immunology Director, Molecular Immunomodulation Program, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY

Track01:Stem Cells

The most well-established and widely used stem cell treatment is thetransplantationof blood stem cells to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers. Since the 1970s,skin stem cellshave been used to grow skin grafts for patients with severe burns on very large areas of the body. Only a few clinical centers are able to carry out this treatment and it is usually reserved for patients with life-threatening burns. It is also not a perfect solution: the new skin has no hair follicles or sweat glands. Research aimed at improving the technique is ongoing.

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Track 02: Stem Cell Banking:

Stem Cell Banking is a facility that preserves stem cells derived from amniotic fluid for future use. Stem cell samples in private or family banks are preserved precisely for use by the individual person from whom such cells have been collected and the banking costs are paid by such person. The sample can later be retrieved only by that individual and for the use by such individual or, in many cases, by his or her first-degree blood relatives.

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Track 03: Stem Cell Therapy:

Autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures. Adult stem cells are frequently used in medical therapies, for example in bone marrow transplantation. Human embryonic stem cells may be grown in vivo and stimulated to produce pancreatic -cells and later transplanted to the patient. Its success depends on response of the patients immune system and ability of the transplanted cells to proliferate, differentiate and integrate with the target tissue.

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4th InternationalConference on Plant GenomicsJuly 14-15, 2016 Brisbane, Australia; 8thWorld Congress on Stem Cell ResearchMarch 20-22, 2017 Orlando, USA; 7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK; 2nd InternationalConference on Tissue preservation and BiobankingSeptember 12-13, 2016 Philadelphia, USA, USA;World Congress on Human GeneticsOctober 31- November 02, 2016 Valencia, Spain; 12thEuro Biotechnology CongressNovember 7-9, 2016 Alicante, Spain; 2nd InternationalConference on Germplasm of Ornamentals, Aug 8-12, 2016, Atlanta, USA; 7th Internationalconference on Crop Science, Aug 1419 2016, Beijing, China;Plant Epigenetics: From Genotype to Phenotype, Feb 1519 2016, Taos, USA;Germline Stem Cells Conference, June 1921 2016, San Francisco, USA;Conference on Water Stressin Plants, 29 May 3 June 2016, Ormont-Dessus, Switzerland

Track 04: Novel Stem Cell Technologies:

Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians and offers hope of effective treatment for a variety of malignant and non-malignant diseases. Stem cells are defined as totipotent progenitor cells capable of self-renewal and multilineage differentiation. Stem cells survive well and show stable division in culture, making them ideal targets for in vitro manipulation. Although early research has focused on haematopoietic stem cells, stem cells have also been recognised in other sites. Research into solid tissue stem cells has not made the same progress as that on haematopoietic stem cells.

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Track 05: Stem Cell Treatment:

Bone marrow transplant is the most extensively used stem-cell treatment, but some treatment derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.

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7th InternationalConference on BioinformaticsOctober 27-28, 2016 Chicago, USA; InternationalConference on Synthetic BiologySeptember 28-30, 2015 Houston, USA; 7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK; 4th InternationalConference on Integrative BiologyJuly 18-20, 2016 Berlin, Germany; 1st InternationalConference on Pharmaceutical BioinformaticsJan 2426 2016, Pattaya, Thailand; EMBL Conference: TheEpitranscriptome, Apr 2022 2016, Heidelberg, Germany; 2016Whole-Cell ModelingSummer School, Apr 38 2016, Barcelona, Spain; 3rd InternationalMolecular Pathological Epidemiology, May 1213 2016, Boston, USA; 5thDrug FormulationSummit, Jan 2527 2016, Philadelphia, USA

Track 06: Stem cell apoptosis and signal transduction:

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility that defects in apoptotic programs contribute to treatment failure. Because the same mutations that suppress apoptosis during tumor development also reduce treatment sensitivity, apoptosis provides a conceptual framework to link cancer genetics with cancer therapy.

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Track 07: Stem Cell Biomarkers:

Molecular biomarkers serve as valuable tools to classify and isolate embryonic stem cells (ESCs) and to monitor their differentiation state by antibody-based techniques. ESCs can give rise to any adult cell type and thus offer enormous potential for regenerative medicine and drug discovery. A number of biomarkers, such as certain cell surface antigens, are used to assign pluripotent ESCs; however, accumulating evidence suggests that ESCs are heterogeneous in morphology, phenotype and function, thereby classified into subpopulations characterized by multiple sets of molecular biomarkers.

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Track 08: Cellular therapies:

Cellular therapy also called Cell therapy is therapy in which cellular material is injected into a patient, this generally means intact, living cells. For example, T cells capable of fighting cancer cells via cell-mediated immunity may be injected in the course of immunotherapy.

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Track 09: Stem cells and cancer:

Cancer can be defined as a disease in which a group of abnormal cells grow uncontrollably by disregarding the normal rules of cell division. Normal cells are constantly subject to signals that dictate whether the cells should divide, differentiate into another cell or die. Cancer cells develop a degree of anatomy from these signals, resulting in uncontrolled growth and proliferation. If this proliferation is allowed to continue and spread, it can be fatal.

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Track 10: Embryonic stem cells:

Embryonic stem cells have a major potential for studying early steps of development and for use in cell therapy. In many situations, however, it will be necessary to genetically engineer these cells. A novel generation of lentivectors which permit easy genetic engineering of mouse and human embryonic stem cells.

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Track 11: Cell differentiation and disease modeling:

Cellular differentiation is the progression, whereas a cell changes from one cell type to another. Variation occurs numerous times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiationalmost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5thInternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26thEuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7thEuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches toVaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 12: Tissue engineering:

Tissue Engineering is the study of the growth of new connective tissues, or organs, from cells and a collagenous scaffold to produce a fully functional organ for implantation back into the donor host. Powerful developments in the multidisciplinary field of tissue engineering have produced a novel set of tissue replacement parts and implementation approaches. Scientific advances in biomaterials, stem cells, growth and differentiation factors, and biomimetic environments have created unique opportunities to fabricate tissues in the laboratory from combinations of engineered extracellular matrices cells, and biologically active molecules.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5thInternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26thEuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7thEuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches toVaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 13: Stem cell plasticity and reprogramming:

Stem cell plasticity denotes to the potential of stem cells to give rise to cell types, previously considered outside their normal repertoire of differentiation for the location where they are found. Included under this umbrella title is often the process of transdifferentiation the conversion of one differentiated cell type into another, and metaplasia the conversion of one tissue type into another. From the point of view of this entry, some metaplasias have a clinical significance because they predispose individuals to the development of cancer.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

InternationalConference on Case ReportsMarch 31-April 02, 2016 Valencia, Spain; 2nd International Meeting onClinical Case ReportsApril 18-20, 2016 Dubai, UAE; 3rd Experts Meeting onMedical Case ReportsMay 09-11, 2016 New Orleans, Louisiana, USA; 12thEuro BiotechnologyCongress November 7-9, 2016 Alicante, Spain; 2nd International Conference onTissue preservation and BiobankingSeptember 12-13, 2016 Philadelphia, USA; 11thWorld Conference BioethicsOctober 20-22, 2015 Naples, Italy;Annual Conference Health Law and Bioethics, May 6-7 2016 Cambridge, MA, USA; 27th Maclean Conference on Clinical Medical Ethics, Nov 13-14, 2015, Chicago, USA; CFP: Global Forum on Bioethics in Research, Nov 3-4, 2015, Annecy, France

Track 14: Gene therapy and stem cells

Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease. Gene therapy could be a way to fix a genetic problem at its source. The polymers are either expressed as proteins, interfere with protein expression, or possibly correct genetic mutations. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient's cells instead of using drugs or surgery.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

Track 15: Tumour cell science:

An abnormal mass of tissue. Tumors are a classic sign of inflammation, and can be benign or malignant. Tomour usually reflect the kind of tissue they arise in. Treatment is also specific to the location and type of the tumor. Benign tumors can sometimes simply be ignored, cancerous tumors; options include chemotherapy, radiation, and surgery.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

Track 16: Reprogramming stem cells: computational biology

Computational Biology, sometimes referred to as bioinformatics, is the science of using biological data to develop algorithms and relations among various biological systems. Bioinformatics groups use computational methods to explore the molecular mechanisms underpinning stem cells. To accomplish this bioinformaticsdevelop and apply advanced analysis techniques that make it possible to dissect complex collections of data from a wide range of technologies and sources.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

The fields of stem cell biology and regenerative medicine research are fundamentally about understanding dynamic cellular processes such as development, reprogramming, repair, differentiation and the loss, acquisition or maintenance of pluripotency. In order to precisely decipher these processes at a molecular level, it is critical to identify and study key regulatory genes and transcriptional circuits. Modern high-throughput molecular profiling technologies provide a powerful approach to addressing these questions as they allow the profiling of tens of thousands of gene products in a single experiment. Whereas bioinformatics is used to interpret the information produced by such technologies.

Related Stem Cell Conferences|Stem Cell Congress|Cell and Stem Cell Conferences|Conference Series LLC

8th World Congress on Cell & Stem Cell Research

The success of the 7 Cell Science conferences series has given us the prospect to bring the gathering one more time for our 8thWorld Congress 2017 meet in Orlando, USA. Since its commencement in 2011 cell science series has perceived around 750 researchers of great potentials and outstanding research presentations around the globe. The awareness of stem cells and its application is increasing among the general population that also in parallel offers hope and add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

Stem Cell Research-2017has the goal to fill the prevailing gaps in the transformation of this science of hope to promptly serve solutions to all in the need.World Congress 2017 will have an anticipated participation of 100-120 delegates from around the world to discuss the conference goal.

History of Stem cells Research

Stem cells have an interesting history, in the mid-1800s it was revealed that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Efforts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the capacity to generate blood cells. In 1968, the first bone marrow transplant was achieved successfully to treat two siblings with severe combined immunodeficiency. Other significant events in stem cell research include:

1978: Stem cells were discovered in human cord blood 1981: First in vitro stem cell line developed from mice 1988: Embryonic stem cell lines created from a hamster 1995: First embryonic stem cell line derived from a primate 1997: Cloned lamb from stem cells 1997: Leukaemia origin found as haematopoietic stem cell, indicating possible proof of cancer stem cells

Funding in USA:

No federal law forever did embargo stem cell research in the United States, but only placed restrictions on funding and use, under Congress's power to spend. By executive order on March 9, 2009, President Barack Obama removed certain restrictions on federal funding for research involving new lines of humanembryonic stem cells. Prior to President Obama's executive order, federal funding was limited to non-embryonic stem cell research and embryonic stem cell research based uponembryonic stem celllines in existence prior to August 9, 2001. In 2011, a United States District Court "threw out a lawsuit that challenged the use of federal funds for embryonic stem cell research.

Members Associated with Stem Cell Research:

Discussion on Development, Regeneration, and Stem Cell Biology takes an interdisciplinary approach to understanding the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex fully patterned adult organism, as well as the intimately related question of how adult structures regenerate. Stem cells play critical roles both during embryonic development and in later renewal and repair. More than 65 faculties in Philadelphia from both basic science and clinical departments in the Division of Biological Sciences belong to Development, Regeneration, and Stem Cell Biology. Their research uses traditional model species including nematode worms, fruit-flies, Arabidopsis, zebrafish, amphibians, chick and mouse as well as non-traditional model systems such as lampreys and cephalopods. Areas of research focus include stem cell biology, regeneration, developmental genetics, and cellular basis of development, developmental neurobiology, and evo-devo (Evolutionary developmental biology).

Stem Cell Market Value:

Worldwide many companies are developing and marketing specialized cell culture media, cell separation products, instruments and other reagents for life sciences research. We are providing a unique platform for the discussions between academia and business.

Global Tissue Engineering & Cell Therapy Market, By Region, 2009 2018

$Million

Why to attend???

Stem Cell Research-2017 could be an outstanding event that brings along a novel and International mixture of researchers, doctors, leading universities and stem cell analysis establishments creating the conference an ideal platform to share knowledge, adoptive collaborations across trade and world, and assess rising technologies across the world. World-renowned speakers, the most recent techniques, tactics, and the newest updates in cell science fields are assurances of this conference.

A Unique Opportunity for Advertisers and Sponsors at this International event:

http://stemcell.omicsgroup.com/sponsors.php

UAS Major Universities which deals with Stem Cell Research

University of Washington/Hutchinson Cancer Center

Oregon Stem Cell Center

University of California Davis

University of California San Francisco

University of California Berkeley

Stanford University

Mayo Clinic

Major Stem Cell Organization Worldwide:

Norwegian Center for Stem Cell Research

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Multipotent Cell-Secreted Extracellular Matrix Supports Cartilage Formation Histogen to present at International Cartilage Repair Society 2015

CHICAGO, May 8, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its human extracellular matrix (hECM) material in the promotion of cartilage regeneration during the International Cartilage Repair Society (ICRS) 2015 Meeting, taking place May 8-11, 2015 in Chicago, IL. The orthobiologic applications of all of Histogen's products are being developed by its worldwide joint venture, PUR Biologics LLC.

Histogen has previously shown that hypoxia-induced multipotent cells produce soluble and insoluble materials that contain components associated with stem cell niches in the body and with scarless healing. These proteins include a variety of laminins, osteonectin, decorin, hyaluronic acid, collagen type IV, SPARC, CXCL12, NID1, NID2, NOTCH2, tenascin, thrombospondin, fibronectin, versican, and fibrillin-2. In vitro studies further demonstrated that the CCM and ECM promote the adhesion, proliferation and migration of bone marrow-derived human mesenchymal stem cells (MSCs).

In this latest research, in vivo studies with the hECM were undertaken to determine their potential as orthobiologics. Rabbit studies demonstrated the potential of the hECM to promote regeneration and repair of full-thickness articular cartilage defects. Eight weeks following hECM treatment of femoral osteochondral defects, mature bone and hyaline cartilage formation was seen, exemplified by the presence of a tide mark and integration into the adjacent cartilage. This work is currently being repeated in a goat cartilage defect model, with similar results to date.

"The efficacy we have seen with the multipotent cell-secreted ECM in bone and cartilage regeneration is unprecedented," said Ryan Fernan, CEO of PUR Biologics. "The preclinical work overwhelmingly supports use of the material as an orthobiologic to reduce inflammation and promote cartilage regeneration in the articulating joint and intervertebral spinal disc. We look forward to entering human trials for these indications, as well as to continuing our research on utilizing the product for soft tissue repair in a variety of sports injuries."

Histogen's cell conditioned media (CCM) and hECM were also evaluated in an ex vivo rabbit intervertebral spinal disc model to study the effects of these materials in an environment where an extensive inflammatory response was induced by thrombin injection. Compared to untreated controls, both the CCM and ECM treatment significantly down regulated the expression of the inflammatory cytokine genes IL-1, IL-6, TNF-alpha, as well as the genes encoding the extracellular matrix degrading enzymes MMP3, and ADAMTS4, while upregulating aggrecan expression in the annulus fibrosus and nucleus pulposus tissue.

Dr. Gail Naughton, CEO of Histogen, will present "Human Cell Conditioned Media and Extracellular Matrix Reduce Inflammation and Support Hyaline Cartilage Formation" at the ICRS 2015 meeting in Chicago on May 9, 2015. Following the event, the presentation will be available upon request.

About PUR Biologics PUR Biologics is dedicated to providing regenerative biologic solutions to address musculoskeletal surgical needs, including spine, dental, ligament and medical device coating applications. In addition to distribution of approved allograft and biologic products, PUR is focused on development of next-generation orthopedic products based upon human protein and growth factor materials for bone and tissue regeneration. For more information visit http://www.purbiologics.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Novel Immunomodulatory Treatment Induces Apoptosis in Melanoma Histogen to present data at 2015 Society of Investigative Dermatology Annual Meeting

ATLANTA, May 6, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its 105F immunomodulatory treatment candidate for melanoma during the 2015 Society of Investigative Dermatology (SID) Annual Meeting, taking place May 6-9, 2015 in Atlanta, GA.

Histogen has previously shown that hypoxia-induced multipotent cells produce a soluble material with anti-oncologic properties, with potential benefit in the treatment of a wide range of cancers. Studies to characterize the active components of the material have identified a low molecular weight fraction (105F) which directly induces apoptosis, or controlled cell death, in 21 human cancer cell lines. In its latest research, Histogen sought to further examine the mechanism of action of 105F in melanoma through in vitro and in vivo studies.

After treatment with 105F, melanoma cells were shown to release Interleukin 6 (IL-6) and TNF a, pro-inflammatory cytokines acting as signals to the immune system. This induction of an immune "flare" in combination with tumor cell apoptosis could be critically important in recruiting immune cells to the tumor for cytotoxic attack.

"We were excited to see the dual activity of 105F, both directly inducing cancer cell death and activating an anti-tumorigenic immune response to reduce metastatic disease," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results represent a potential treatment for melanoma and other solid tumors that works through multiple channels to eliminate cancer cells, but is not toxic to the body's healthy cells."

An in vivo model of lung metastasis in C57Bl/6 mice further showed the efficacy of 105F in the treatment of melanoma. Daily intravenous injections of 105F over 14 days resulted in a significant (p=0.0049) reduction in lesions and marked immune cell infiltration as compared to controls.

Dr. Naughton will present "105F is a novel immunoadaptive treatment candidate for melanoma that induces apoptosis and the secretion of pro-inflammatory IL-6" at the 2015 SID Annual Meeting in Atlanta beginning May 6, 2015. Following the event, the presentation will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Histogen's Composition for Oncology Treatments Receives US Patent

SAN DIEGO, October 8, 2014 - Histogen Oncology, a company developing innovative cancer therapies based on Histogen's regenerative medicine technology, today announced that the United States Patent & Trademark Office has issued patent 12/363,479 entitled "Extracellular matrix compositions for the treatment of cancer" to Histogen.

The patent, which is the fifth U.S. patent issued to Histogen, covers the soluble and insoluble compositions of proteins and cofactors that are secreted by multipotent stem cells through Histogen's technology process for use in the treatment of cancer. The patent claims support of the use of the compositions alone or as a delivery system for traditional chemotherapeutic agents.

Through the recent formation and funding of the Histogen Oncology joint venture, research and development of the unique, naturally secreted compositions is progressing toward a Phase I clinical trial for end stage pancreatic cancer.

"We are pleased about the timely issuance of our U.S. patent for the treatment of cancer," said Dr. Gail K. Naughton, Histogen CEO and Chairman of the Board. "Our collaborations with top institutions continue to produce mounting evidence supporting the unique mechanism of action of our secreted material in preventing metastasis and reducing tumor load while having no toxic affect on normal cells."

Histogen's composition has shown effectiveness in inhibiting over 21 human cancer cell lines both in vitro as well as in animal models. The mechanism of action of the secreted material is through the induction of apoptosis (controlled cell death) primarily in malignant cells, so there is little to no toxicity to normal cells. Histogen Oncology is studying the efficacy of a small molecular weight fraction of the cell secreted composition as a stand alone treatment as well as in combination therapy to evaluate whether effectiveness can be demonstrated with less toxic drug doses.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Oncology Created to Develop Novel Biologic Cancer Treatments Histogen, Inc. and Wylde, LLC Form Joint Venture

SAN DIEGO, July 8, 2014 - Histogen Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, has partnered with Southern California medical device group Wylde, LLC to create Histogen Oncology. This joint venture will focus on the development of unique cell-derived materials for cancer applications.

Under this joint venture, Histogen Oncology has acquired exclusive rights to Histogen's human multipotent cell conditioned media (CCM) and extracellular matrix (ECM) materials, as well as their derivatives, for oncology applications throughout North America. Histogen Oncology's initial clinical focus is pancreatic cancer, a highly treatment-resistant cancer in which a sub-fraction of the CCM has shown substantial preclinical promise.

"We have been very impressed with the results of Histogen's preliminary oncology work, not only because of the significant survival benefit but also because it is a naturally-derived material that is showing no toxicity," said Christopher Wiggins of Wylde, LLC. "There are so many patients out there who are not candidates for existing therapies due to the toxic nature of available drugs. This is particularly true in pancreatic cancer, where 80% of people diagnosed already have stage four disease."

In post-resection nude mouse models, intravenous treatment with the CCM sub-fraction resulted in prolonged survival by more than three fold in a majority of treated animals. In non-resection models, more than 50% of treated mice lived twice as long as the control. These results point to a potentially significant outcome for pancreatic cancer patients, and Histogen Oncology intends to progress the material toward a Phase I clinical trial for no-option pancreatic cancer patients in the coming 18 months.

Research on the mechanism responsible for cancer cell inhibition by the CCM shows the upregulation of Caspase 9 and cleaved Caspase 3, which causes cancer cells to enter apoptosis, or programmed cell death.

"The activity of the CCM sub-fraction is unique in a number of ways. Whereas most cancer therapies target rapidly dividing cells but not cancer stem cells, the inhibitory effect of this material is seen in malignant cells and circulating tumor cells as well," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen, Inc. "In addition, the activity is selective for malignant cells, supporting the proliferation of human dermal fibroblasts, embryonic stem cells and mesenchymal stem cells, while inhibiting tumor growth."

Histogen Oncology will be supported by Histogen's research group and funded by Wylde, LLC., made up of experts from the surgery and medical device industries. The creation of this joint venture allows for dedicated development of the CCM sub-fraction as a cancer treatment, as Histogen continues to allocate resources to the Company's revenue-generating aesthetic and promising therapeutic programs.

"We are extremely excited to fuel and push the next stage of development for this innovative and potentially life-saving therapy," said Wiggins. "The next generation of cancer treatment will have cell-signaling at its core, be beneficial in combination with existing therapies as well as stand alone, and provide an option to patients who currently have none. We believe Histogen's material has all of those characteristics and more."

About Histogen Aesthetics Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Aesthetics Acquires CellCeuticals Biomedical Skin Treatments

SAN DIEGO, March 10, 2014 - Histogen Aesthetics, a subsidiary of regenerative medicine company Histogen, Inc. focused on skin care and cosmeceuticals, announced today that the Company has acquired the CellCeuticals Biomedical Skin Treatments line of skincare products.

Histogen Aesthetics will continue sales of the eleven existing CellCeuticals Biomedical Skin Treatments skincare products, while bringing new innovation to the line through the addition of a unique regenerative medicine technology, working to improve skin aging at a cellular level.

"We have long admired the science, clinical data and elegant formulas behind the CellCeuticals line, and see it as an ideal fit for our recently revitalized aesthetics subsidiary," said Dr. Gail K. Naughton, CEO and Chairman of Histogen, Inc. "We are very excited to begin infusing unique cell-signaling factors into the CellCeuticals regimen, to truly transform skin one cell at a time."

Dr. Naughton has spent more than 30 years in tissue engineering and regenerative medicine, and holds over 100 patents in the field. She founded Histogen in 2007, focused on developing therapies that work to stimulate the stem cells in the body to regenerate tissues and organs. Through this work, she has also seen how different compositions of human proteins can have cosmetic benefits, particularly in anti-aging and rejuvenation.

"I am pleased that the CellCeuticals Biomedical Skin Treatments will evolve, and see Histogen Aesthetics as an excellent home for this innovative product line," said Paul Scott Premo, co-founder of CellCeuticals Skin Care, Inc. "I believe the addition of this regenerative medicine technology will be the opportunity to introduce a new generation of products that are the vanguard of regenerative skin care."

The CellCeuticals system is made up of eleven distinctive products including the Extremely Gentle Skin Cleanser, CellGenesis Regenerative Skin Treatment, and PhotoDefense Color Radiance SPF55+ with proprietary and patented PhotoPlex technology. The line is currently available at retailers including QVC.com, Dermstore.com, and Nordstrom.com, as well as http://www.cellceuticalskincare.com.

About Histogen Aesthetics Histogen Aesthetics LLC, formed in 2008 as a subsidiary of Histogen, Inc., focuses on the development of innovative skin care products utilizing regenerative medicine technology. Histogen Aesthetics' technology is based on the expertise of founder Dr. Gail K. Naughton, in which fibroblasts are grown under unique conditions, producing a complex of naturally-secreted proteins and synergistic bio-products known to stimulate skin cells to regenerate and rejuvenate tissues. In 2014, Histogen Aesthetics acquired CellCeuticals Biomedical Skin Treatments, a line of scientifically-proven products that reactivate cells to help aging skin perform and look healthier and younger. For more information, visit http://www.cellceuticalskincare.com.

About Suneva Medical, Inc. Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process is also being researched for oncology applications, and in orthopedics through joint venture PUR Biologics, LLC. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen and Suneva Medical Expand License for Cell Conditioned Media-based Aesthetic Products Internationally

SAN DIEGO, CA, January 14, 2014 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, today announced that they have entered into an international license agreement with Suneva Medical, Inc. for physician-dispensed aesthetic products containing Histogen's proprietary multipotent cell conditioned media (CCM).

This agreement is an amendment to the existing license between Histogen and Suneva Medical, through which Suneva has exclusively licensed the Regenica skincare line within the United States since February 2012. Under the terms of the international agreement, Suneva Medical is now the exclusive licensee for the distribution of Regenica through the physician-dispensed channel in Europe, most of Asia, South America, Canada, Australia, and the Middle East.

"Not only has Suneva had sales success, but they have generated enthusiasm around the Regenica product line and our technology here in the US," said Gail K. Naughton, Ph.D., CEO and Chairman of the Board of Histogen. "We are excited about expanding our skincare partnership internationally, and look forward to an exciting year for Regenica."

Regenica contains Histogen's proprietary Multipotent Cell Conditioned Media, made up of soluble cell-signaing proteins and growth factors which support the body's epidermal stem cells and renew skin throughout life. Through Histogen's technology process, which mimics the embryonic environment including conditions of low oxygen and suspension, cells are triggered to become multipotent, and naturally produce these proteins associated with skin renewal and scarless healing.

"We believe that Regenica truly is the next generation in growth factor technology, and we are extremely pleased that the products will now have a presence around the world," said Nicholas L. Teti, Jr., Chairman and Chief Executive Officer of Suneva Medical. "Our relationship with Histogen in the US physician market has been a valuable asset to Suneva, and has laid the groundwork for international success."

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

About Suneva Medical, Inc. Suneva Medical, Inc. is a privately-held aesthetics company focused on developing, manufacturing and commercializing novel, differentiated products for the general dermatology and aesthetic markets. The company currently markets Artefill in the US, Korea, Singapore and Vietnam; Refissa and Regenica Skincare in the U.S.; and Bellafill in Canada. For more information, visit http://www.sunevamedical.com.

Regenica is a trademark of Suneva Medical, Inc. The Multipotent Cell Conditioned Media Complex is covered by U.S. patents #8,257,947 and #8,524,494.

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Multipotent Stem Cell Proteins Support Soft Tissue Regeneration Histogen to present data at TERMIS AM Annual Conference in Atlanta

ATLANTA, November 13, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that Dr. Michael Zimber will give a podium presentation entitled "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration" today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Americas Annual Meeting in Atlanta, GA.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen has developed a human extracellular matrix (hECM) material composed of stem cell-associated proteins including SPARC, decorin, collagens I,III,IV, V, fibronectin, fibrillin, laminins, and hyaluronic acid. The hECM's distinctive composition of growth factors and other proteins are known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

Histogen sought to examine whether the hECM may promote scarless healing in full thickness wounds, similar to that seen in fetal healing, using a variety of forms of the material, including hollow spheres to maximize void fill volume. In preclinical studies, all hECM-treated wounds healed rapidly with minimum contractions, and the hECM microspheres had a statistically significant improvement in healing as compared to the controls (p<0.05) and produced a 25% thicker dermis. In addition, hECM applied topically after microneedling resulted in up to a 3X dermal thickening.

"We are very pleased that our propriety materials produced by hypoxia-induced human multipotent stem cells have shown significant healing results in both soft and hard tissues," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results open new therapeutic markets, show tremendous potential for our material in cutaneous wound care and orthopedics, as well as support the expansion of our aesthetic pipeline to include soft tissue fillers."

In addition to "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration", Dr. Zimber will also be presenting "Human Multipotent Stem Cell Proteins Support Osteogenesis In Vitro" during the TERMIS AM Annual Meeting taking place November 10-13, 2013 in Atlanta. Following the event, these presentations will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Multipotent Stem Cell Proteins Support Rejuvenation while Inhibiting Skin Cancer Histogen to present data at TERMIS AP Annual Conference in Shanghai

San Diego, October 24, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that the Company's Chairman and CEO, Dr. Gail Naughton, will present today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Asia Pacific Annual Meeting in Shanghai, China.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen is uniquely able to trigger the de-differentiation of skin cells into multipotent stem cells without genetic manipulation. The cells express key stem cell markers including Oct4, Sox2 and Nanog, and secrete a distinctive composition of growth factors and other proteins known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

It is the soluble and insoluble compositions of multipotent proteins and growth factors resulting from this process that have been shown to both promote skin regeneration and induce controlled cell death in multiple skin cancers.

"The anti-aging and rejuvenation benefits of human multipotent stem cell proteins have been shown in several clinical studies, and have resulted in the material's use as a thriving next-generation ingredient for skin care," said Dr. Naughton. "In parallel, we have also been studying the anti-cancer activity of these proteins, and have shown that, just as in the embryonic environment, they support normal tissue growth while resulting in the controlled death of cancer cells".

In vitro studies performed with Histogen's material have shown reduction in Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma, and Melanoma cell number through the mechanism of apoptosis, or controlled cell death, induced by the upregulation of Caspase in these cancer cells. In one in vivo model, melanoma load was reduced by up to 80% versus the control (p<0.05) by the addition of the insoluble multipotent stem cell proteins, and a dose response curve was seen. Similar inhibition was seen with SCC. In subcutaneous mouse experiments, tumor growth was inhibited by 70-90%.

"Human Multipotent Stem Cell Proteins Stimulate Skin Regeneration While Inducing Skin Cancer Cell Apotosis" will be presented by Dr. Naughton during the TERMIS AP Annual Meeting taking place October 23-26, 2013 in Shanghai. Further information and data on the ability of multipotent stem cell proteins to induce apoptosis in skin cancers can be found in the publication Journal of Cancer Therapy at file.scirp.org/Html/1-8901700_33923.htm.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Histogen to present at 2013 STEM CELL MEETING ON THE MESA

San Diego, October 11, 2013 - Histogen, Inc., a regenerative medicine company developing therapies for conditions including hair loss and cancer, announced today that Histogen CEO Gail K. Naughton, Ph.D. will give a company presentation at the 3rd Annual Regen Med Partnering Forum, part of the Stem Cell Meeting on the Mesa to be held October 14-16 in La Jolla, CA.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation.

"It is an exciting time for Histogen, as we continue to move the technology forward with expanded partnerships in skincare, compelling clinical data in both male and female hair loss, and early but exciting results in orthopedics," said Dr. Naughton. "We look forward to sharing our story during the Stem Cell Meeting on the Mesa, and to progressing our products even further through growing relationships with industry leaders and through our potential merger with Stratus Media to form publicly-traded Restorgenex."

Organized by the Alliance for Regenerative Medicine (ARM), the California Institute for Regenerative Medicine (CIRM) and the Sanford Consortium for Regenerative Medicine, the 2013 Stem Cell Meeting on the Mesa is a three-day conference aimed at bringing together senior members of the regenerative medicine industry with the scientific research community to advance stem cell science into cures. The Regen Med Partnering Forum, held October 14 &15 at the Estancia La Jolla Hotel, is the only partnering meeting organized specifically for the regenerative medicine and advanced therapies industry.

The following are specific details regarding Histogen's presentation at the conference:

Event: Regen Med Partnering Forum - 2013 Stem Cell Meeting on the Mesa Date: October 14, 2013 Time: 3:15pm Location: Estancia La Jolla Hotel & Spa, 9700 North Torrey Pines Road, La Jolla

A live video webcast of all company presentations will be available at: stemcellmeetingonthemesa.com/webcast and will also be published on ARM's website shortly after the event. Histogen will also make a copy of Dr. Naughton's presentation available at http://www.histogen.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Stratus Media Group and Histogen Execute Letter of Intent for Biotechnology Merger

LOS ANGELES, October 07, 2013 - Stratus Media Group, Inc. (OTCQB:SMDI) announced today that it was planning to expand its entrance into the biotechnology industry with the execution of a letter of intent between the Company and Histogen, Inc., a regenerative medicine company developing innovative therapies for conditions including hair loss and cancer.

The non-binding letter of intent outlines the primary terms of a merger of San Diego-based Histogen into Stratus, to be renamed Restorgenex Corporation. The letter of intent has been approved by the board of directors of both companies, and the parties are engaged in completing a formal merger agreement.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products.

"Histogen's technology platform opens a spectrum of potential product opportunities in both aesthetics and therapeutics, an ideal fit with our vision for Restorgenex," said Sol J. Barer, Ph.D., who will assume the position of Chairman of the Board of Restorgenex effective November 1, 2013. "The expertise of the Histogen team in developing regenerative products from concept to market, along with the success Histogen has already found in skincare partnering, will add significant value to our Company."

Following successful completion of this proposed merger, the company's goal is to build Restorgenex into a world-class cosmeceutical and pharmaceutical company in the large and expanding fields of dermatology and hair restoration. The parties intend to move toward a formal merger agreement in which Histogen would become a wholly-owned subsidiary, Histogen founder Gail K. Naughton, Ph.D. would assume the position of Chief Executive Officer of Restorgenex, and the corporate headquarters of Restorgenex would be located in San Diego. The merger will require, among other things, the satisfaction of customary closing conditions including the approval of Histogen's shareholders.

"I am very excited about the potential of a merger between Histogen and Restorgenex, and look forward to moving into the next stage," said Dr. Naughton. "It is an honor to be working with biotechnology visionaries Dr. Sol Barer and Isaac Blech, and to have them recognize the promise of Histogen's products is a true testament to the unique and exciting nature of our technology."

Dr. Naughton has spent more than 25 years extensively researching the tissue engineering process, holds more than 95 U.S. and foreign patents, and has been honored for her pioneering work in the field by prestigious organizations including receiving the Intellectual Property Owners Association Inventor of the Year Award.

Prior to founding Histogen in 2007, Dr. Naughton oversaw the design and development of the world's first up-scaled manufacturing facility for tissue engineered products, was pivotal in raising over $350M from the public market and corporate partnerships, and brought four human cell-based products from concept through FDA approval and market launch as President of Advanced Tissue Sciences.

"I believe the potential acquisition of Histogen, and the expertise and vision Dr. Naughton will bring as Chief Executive Officer will be a tremendous asset in ushering the Company into the biotechnology industry," said Jerold Rubinstein, current Chairman and Chief Executive Officer of Stratus.

http://www.histogen.com http://www.stratusmediagroup.com

Forward-Looking Statements Statements in this press release relating to plans, strategies, projections of results, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and the Securities Acts of 1933 and 1934. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors. Although the company's management believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee future results, performance or achievements. The company has no obligation to update these forward-looking statements.

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Histogen - About Histogen - Latest news, upcoming events ...

Stem Cell 100 is formulated to rejuvenate your body and slow the aging process to help you feel and function more like a young person. This can help you feel better, look younger and improve your health. Most of the cells in your body lose function with age. Everyone has special cells called adult stem cells which are needed to rejuvenate damaged and old tissues, but adult stem cells themselves are also aging. Until now there was not much you could do about it. Stem Cell 100 rejuvenates adult stem cells and their micro-environments. Stem Cell 100+ is a more advanced and faster acting version of Stem Cell 100.

Developed by experts in the anti-aging field, patent-pending Stem Cell 100 is the only supplement proven to double maximum lifespan of an animal model. No other product or therapy including caloric restriction even comes close.

SK of Santa Fe, NM

I have been using Stem Cell 100 for about one year. Initially I noticed a boost in energy level, which now remains steady-hence not noticed I have experienced no adverse effects from taking this product. I heartily recommend Stem Cell 100 and plan to continue on it.

Leslie

Stem Cell 100 has made a noticeable difference in me, including turning my gray hair back to its original color, which supposedly is impossible. The reversal of the gray hair to original color began a couple of months after starting the pill. After about 10 months, the gray hair is mostly gone. At the current rate of improvement, I expect my hair to completely be back to its original color within 1 to 2 months. I think my beard will take longer, but it was the first to gray. Also, my skin became smoother and younger looking. The skin and hair rely heavily on stem cells, and they seem to benefit strongly from this product. I'm so excited about telling people my results because there is nothing that can reverse the graying of hair. It will give me evidence that this supplement thing is really powerful. Unfortunately, I don't have before and after pictures because I didn't read any claims that the product would affect hair color. I would just say that I'm a person who totally believes that it does me no good to imagine things or interpret tings in a way favorable to what I want to believe. When I'm convinced enough to make a statement, you can count on it.

Joey of San Diego, CA

I am a 48 year old working woman. A friend of mine introduced me to Stem Cell 100. After taking Stem Cell 100 for about 4 months my anxiety level has really been diminished. Its a great supplement and I would recommend it to everyone!

Paul of San Diego, CA

I am an active 61 year old man in excellent health, but had experienced a serious drop in my energy level at the time I enrolled in a 4-month trial of Stem Cell 100. Within a month, my energy increased noticeably and I began to take to my physical activities (running, cycling) with a renewed enthusiasm and intensity level. My mood began to elevate steadily, and soon I had even lost those few stubborn pounds that had eluded me for years. I am very enthusiastic about Stem Cell 100. I look forward to continuing with the new, improved formulation, and would not hesitate to recommend it.

Mike, Texas

After taking the Stem Cell 100 for the last month my sinuses have also cleared, unplugging my ears for the first time since mid September.

Willie, California

As I was sprinting this morning around 6:00am I noticed that I was not hurting anymore! I have been having sore knees, ankles, hamstrings and back for the last couple of years. I usually just ran through it, but I noticed since I have been taking the Stem Cell 100 capsules for about 45 days now, those nagging pains are gone away!

Tom, Australia

Only after about 2-3 weeks of taking Stem Cell 100 my eye sight returned back to a level where I did not need glasses to work on my computer monitors. My eyes had always been good but had started to deteriorate about a year ago where 50% of the time I had to wear my glasses. I was shocked to find the improvement so quick. I found I was less stressed. No other changes to lifestyle yet a measureable difference. My fingers would sometimes get stiff in the mornings after long days on the keyboard. This stiffness disappeared. Some of my hair is getting darker. I have a full body of hair that had virtually all turned grey but I noticed that some of my hair was starting regrow brown - my original colour. I had some age spots in my left leg that are disappearing. Generally, I feel great.

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Harness the Power of Your Own Stem Cells

Millions of people suffer from chronic conditions of aging and disease. Based on international scientific studies in many academic and industry laboratories, there is new hope that many of the conditions afflicting mankind can some day be cured or greatly improved using stem cell regenerative medicine. Stem Cell 100 offers a way to receive some of the benefits of stem cell therapy today by improving the activity and effectiveness of your own adult stem cells.

Stem Cell 100 Helps to Support:

The statements above have not been reviewed by the FDA. Stem Cell 100 is not a preventive or treatment for any disease.

Help Rejuvenate Your Body by Boosting Your Own Stem Cells

As a child, we are protected from the ravages of aging and can rapidly recover from injury or illness because of the ability of the young regenerative stem cells of children have a superior ability to repair and regenerate most damaged tissues. As we age, our stem cell populations become depleted and/or slowly lose their capacity to repair. Moreover, the micro-environment (i.e. niches) around stem cells becomes less nurturing with age, so cell turnover and repair are further reduced. This natural progression occurs so slowly that we are barely aware of it, but we start to notice the body changes in our 20s, 30s, 40s, and especially after 50 years of age. Stem Cell 100 helps adults regain their youthful regenerative potential by stabilizing stem cell function.

Stem Cell 100 works differently than other stem cell products on the market

You may have seen a number of products that are advertised as stimulating or enhancing the number of stem cells. Each person only has a limited number of stem cells so using them up faster may not be a good strategy. Stem Cell 100 is about improving the effectiveness and longevity of your stem cells as well as preserving the stem cell micro-environment. That should be the goal of any effective stem cell therapy and is what Stem Cell 100 is designed to do and what other stem cell products cannot do.

Stem Cell 100 Extends Drosophila (Fruit Fly) Lifespan

In extensive laboratory testing Stem Cell 100 greatly extended both the average and maximum lifespan of Drosophila fruit flies. The study (see Charts below) included three cages of Drosophila fruit flies that were treated with Stem Cell 100 (Cages T1 to T3) and three cages which were untreated controls (Cages C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females. The experiment showed that median lifespan more than doubled with a 123% increase. While fruit flies are not people they are more like us than you might think. Drosophila have a heart and circulatory system, and the most common cause of death is heart failure. Like humans and other mammals (e.g. mice), it is difficult to increase their lifespan significantly. These observed results outperform every lifespan enhancing treatment ever tested - including experiments using genetic modification and dietary restriction.

The longest living fruit fly receiving Stem Cell 100 lived 89 days compared to the longest living untreated control which lived 48 days. It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation, however, there were many others that lived almost as long so it was not just an aberation. The oldest 5% of the treated fruit flies lived 77% longer than the oldest 5% of the control group. It is also important that the study showed an improved ability of the fruit flies to survive stress and illness at all ages not just during old age. Even after the first few days of the study there were already more of the Stem Cell 100 treated fruit flies alive that survived youth than the control group of untreated fruit flies. For additional information about the study please go to our Longevity page.

Supplement Facts

Stem Cell 100 is a Patent-Pending Life Code Nutraceutical. All Life Code products are nutraceutical grade and provide the best of science along with the balance of nature.

All Life Code products are nutraceutical grade and provide the best of science along with the balance of nature.

Click label to enlarge

Stem Cell 100 Plus+ is a more powerful and faster acting version of Stem Cell 100.

Click label to enlarge

Serving Size: One type O capsule

Servings Per Container: 60 Capsules

Recommended Use: Typical usage of Stem Cell 100 is two capsules per day, preferably at meal times. While both capsules can be taken at the same time, it is preferable to separate the two capsules by at least 4 hours. Since Stem Cell 100 is a potent formulation, do not take more than three capsules per day. One capsule per day may be sufficient for those below 110 pounds.

Recommended Users: Anyone from ages 22 and up could benefit from Stem Cell 100. Those in their 20s and 30s will like the boost in endurance during sports or exercise, while older users will notice better energy and general health with the potential for some weight loss.

Active Ingredients in Stem Cell 100: There are ten herbal components that make up the patent-pending combination in Stem Cell 100. The herbal components are highly extracted natural herbs that are standardized for active components that promote adult stem cells and lower inflammation:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems.

2) Proprietary natural bilberry flavonoids and other compounds from a stabilized nutraceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and silent inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which greatly reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury.

5) Pterocarpus Marsupium, which contains two stable resveratrol analogs which promote stem cells, lower inflammation, and stabilized metabolism.

6) Polygonum Multiflorium stem stem is a popular Chinese herbal tonic that fights premature aging and promotes youthfulness. Polygonum is reported to enhance fertility by improving sperm count in men and egg vitality in women. Polygonum is also widely used in Asia to strengthen muscle and is thus used by many athletes as an essential tonic for providing strength and stamina to the body. Modern research has supported Polygonum multiflorium stem in that animal studies have proven that it can extend lifespan and improve the quality of life. Polygonum appears to protect the liver and brain against damage, perhaps by improving immune and cardiovascular health. The stem sections of Polygonum multiflorium are also calming to the nervous system and promote sounder sleep. Life Code uses a proprietary Polygonum multiflorium stem extract.

7) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In Chinese traditional medicine, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep. Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Modern research indicates that Schisandra berry extracts have a protective effect on the liver and promote immunity. A double-blind human trial suggested that Schisandra berry may help patients with viral hepatitis, which is very prevalent in China. Recent work indicates that the liver is protected by the enhanced production of glutathione peroxidase, which helps detoxify the liver. Life Code uses a proprietary Schisandra berry extract.

8) Fo-Ti Root (aka He-Shou-Wu) is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. Fo-Ti is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor. Legend has it that Professor Li Chung Yun took daily doses of Fo-Ti to live to be 256 and is said to have outlived 23 wives and spawned 11 generations of descendents before his death in 1933. While it is unlikely that he really lived to such an old age there is scientific support for Fo-Ti as beneficial for health and longevity. Like the Indian Keno bark, Fo-ti contains resveratrol analogs and likely acts by various mechanism, which includes liver detoxification and protection of skin from UVB radiation. Life CodeTM uses a proprietary Fo-Ti root extract.

9 ) Camellia sinensis has many bioactive polyphenols including the potent epigallocatechin-3-gallate (EGCG). A 2006 Japanese study published in the Journal of the American Medical Association reports that adults aged 40 to 79 years of age who drank an average of 5 or more cups of tea per day had a significantly lower risk of dying from all causes (23% lower for females and 12% lower for males). The study tracked more than 40,000 adults for up to 11 years and found dramatically lower rates of cardiovascular disease and strokes in those drinking 5 or more cups of tea. Many studies have found that adults drinking 3 or more cups of tea per day have significantly less cancer. Other studies have found that green tea helps protect against age-related cognitive decline, kidney disease, periodontal disease, and type 2 diabetes. Green tea also promotes visceral fat loss and higher endurance levels. Summarizing all of the thousands of studies on tea and tea polyphenols that have been published, it can be concluded that tea polyphenols preserve health and youth. This conclusion is backed up by gene studies showing that tea polyphenols decrease insulin-like growth factor-1 (IGF-1), which is a highly conserved genetic pathway that has been strongly linked to aging in yeast, worms, mice, and humans. If everyone could drink 4 to 5 cups of green tea each day, they could enjoy these important health benefits, but for most people drinking that much green tea can disturb their sleep patterns. Life Code uses a nutraceutical grade green tea extract that has 98% polyphenols and 50% ESCG that provides the polyphenol and ESCG equivalent of 4 to 5 cups of green tea with only 2% of the caffeine. Thus, most or all of the benefits of green tea are provided without concerns about disturbing sleep.

10) Drynaria Rhizome is used extensively in traditional Chinese medicine as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures. Drynaria has also helped in many cases of bleeding gums and tinnitus (ringing in the ears). The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary Drynaria rhizome extract.

Active Ingredients in Stem Cell 100+ There are 11 herbal extracts in Stem Cell 100+ along with two nutraceutical grade vitamins Methyl Folate (5-MTHF) and Methyl B12 that are bioavailable vitamin supplements that are highly potent but rarely found. The highly extracted natural herbs are standardized for active components that promote adult stem cells and lower inflammation and have been tested as a synergistic herbal formulation with the proper dosage of each component:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems. Astragalus has been used for thousands of years in Traditional Chinese Medicine (TCM) to promote cardiovascular and immune health. Astragalus is also known as a primary stimulator of Qi (Life Force). Life Code uses a high quality proprietary TCM extract that tested highest in our longevity experiments.

2) Proprietary natural bilberry flavonoids and other compounds from a stabilized nutraceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and silent inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which promote the vascular system and reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury. Life Code tested supplement with Mass Spec to verify high purity.

5) Genistein, which is an isoflavone phytoestrogen, activates telomerase, metabolic PPARs, autophagy (cell waste disposal), and smooth muscles. It also inhibits DNA methylation and the carbohydrate transporter GLUT1. Life Code tested supplement with Mass Spec to verify high purity.

6) Harataki Extract (aka Terminalia chebula) contains rejuvenating tannin flavonoids that have doubled human cell longevity in culture while maintaining telomere length. In Traditional Indian Medicine, Harataki has been used to treat skin disorders and heart disease, among many other uses.

7) Two stable resveratrol analogs from extracts of Pterocarpus Marsupium, which promote stem cells, less silent inflammation, and better metabolism. Life Code uses a highly purified proprietary source that is only available to Indian doctors. Life Code does not recommend taking resveratrol supplements or synthetic analogs, as these supplements are inherently unstable.

8) He-Shou-Wu is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. He-Shou-Wu is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor. Legend has it that Professor Li Chung Yun took daily doses to live to 256 years and is said to have outlived 23 wives and spawned 11 generations of descendants before his death in 1933. While it is unlikely that he really lived to such an old age, there is scientific support for He-Shou-Wu as beneficial for health and longevity. Life Code uses a proprietary TCM He-Shou-Wu root extract.

9) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In TCM, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep. Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Life Code uses a proprietary TCM extract.

10) Drynaria Rhizome is used extensively in TCM as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures. The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary TCM Drynaria rhizome extract.

11) BioPerine is a proprietary brand of peperine extracted from black pepper. BioPerine has been shown to enhance bioavailability of herbal extracts. Piperine has been shown in rats to have cognitive enhancing effects and to help control silent inflammation.

Safety: The extracts in Stem Cell 100 and Stem Cell 100+ are nutraceutical grade and have been individually tested in both animals and humans without significant safety issues. Those with pre-existing conditions of diabetes or hypertension should coordinate this product with your doctor, as lower blood glucose or reduced blood pressure can result from taking the recommended dose of this product.

Warnings: may lower glucose and/or blood pressure in some individuals. The supplement is not recommended for pregnant, lactating, or hypoglycemic individuals.

References

1. Yu, Q., Y.S. Bai, and J. Lin, [Effect of astragalus injection combined with mesenchymal stem cells transplantation for repairing the Spinal cord injury in rats]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2010. 30(4): p. 393-7.

2. Xu, C.J., et al., [Effect of astragalus polysaccharides on the proliferation and ultrastructure of dog bone marrow stem cells induced into osteoblasts in vitro]. Hua Xi Kou Qiang Yi Xue Za Zhi, 2007. 25(5): p. 432-6.

3. Xu, C.J., et al., [Effects of astragalus polysaccharides-chitosan/polylactic acid scaffolds and bone marrow stem cells on repairing supra-alveolar periodontal defects in dogs]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006. 31(4): p. 512-7.

4. Zhu, X. and B. Zhu, [Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice]. Hua Xi Yi Ke Da Xue Xue Bao, 2001. 32(4): p. 590-2.

5. Qiu, L.H., X.J. Xie, and B.Q. Zhang, Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull, 2010. 33(4): p. 641-6.

6. Araghi-Niknam, M., et al., Pine bark extract reduces platelet aggregation. Integr Med, 2000. 2(2): p. 73-77.

7. Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002. 40(4): p. 158-68.

8. Koch, R., Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res, 2002. 16 Suppl 1: p. S1-5.

9. Rimando, A.M., et al., Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem, 2005. 53(9): p. 3403-7.

10. Manickam, M., et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod, 1997. 60(6): p. 609-10.

11. Grover, J.K., V. Vats, and S.S. Yadav, Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab, 2005. 7(4): p. 414-20.

12. Mao, X.Q., et al., Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model. Acta Pharmacol Sin, 2007. 28(12): p. 1947-56.

13. Schafer, A. and P. Hogger, Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007. 77(1): p. 41-6.

14. Kwak, C.J., et al., Antihypertensive effect of French maritime pine bark extract (Flavangenol): possible involvement of endothelial nitric oxide-dependent vasorelaxation. J Hypertens, 2009. 27(1): p. 92-101.

15. Xue, B., et al., Effect of total flavonoid fraction of Astragalus complanatus R.Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine, 2008.

16. Mizuno, C.S., et al., Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARalpha. Bioorg Med Chem, 2008. 16(7): p. 3800-8.

17. Sato, M., et al., Dietary pine bark extract reduces atherosclerotic lesion development in male ApoE-deficient mice by lowering the serum cholesterol level. Biosci Biotechnol Biochem, 2009. 73(6): p. 1314-7.

18. Kimura, Y. and M. Sumiyoshi, French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless Mice. Photochem Photobiol, 2010.

19. Pavlou, P., et al., In-vivo data on the influence of tobacco smoke and UV light on murine skin. Toxicol Ind Health, 2009. 25(4-5): p. 231-9.

20. Ni, Z., Y. Mu, and O. Gulati, Treatment of melasma with Pycnogenol. Phytother Res, 2002. 16(6): p. 567-71.

21. Bito, T., et al., Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression. Free Radic Biol Med, 2000. 28(2): p. 219-27.

22. Rihn, B., et al., From ancient remedies to modern therapeutics: pine bark uses in skin disorders revisited. Phytother Res, 2001. 15(1): p. 76-8.

23. Saliou, C., et al., Solar ultraviolet-induced erythema in human skin and nuclear factor-kappa-B-dependent gene expression in keratinocytes are modulated by a French maritime pine bark extract. Free Radic Biol Med, 2001. 30(2): p. 154-60.

24. Van Wijk, E.P., R. Van Wijk, and S. Bosman, Using ultra-weak photon emission to determine the effect of oligomeric proanthocyanidins on oxidative stress of human skin. J Photochem Photobiol B, 2010. 98(3): p. 199-206.

25. Haskell, C.F., et al., The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol, 2008. 77(2): p. 113-22.

26. Owen, G.N., et al., The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci, 2008. 11(4): p. 193-8.

27. Yamada, T., et al., Effects of theanine, a unique amino acid in tea leaves, on memory in a rat behavioral test. Biosci Biotechnol Biochem, 2008. 72(5): p. 1356-9.

28. Jia, R.Z., et al., [Neuroprotective effects of Astragulus membranaceus on hypoxia-ischemia brain damage in neonatal rat hippocampus]. Zhongguo Zhong Yao Za Zhi, 2003. 28(12): p. 1174-7.

29. Nathan, P.J., et al., The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother, 2006. 6(2): p. 21-30.

30. Nobre, A.C., A. Rao, and G.N. Owen, L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr, 2008. 17 Suppl 1: p. 167-8.

31. Murakami, S., et al., Effects of oral supplementation with cystine and theanine on the immune function of athletes in endurance exercise: randomized, double-blind, placebo-controlled trial. Biosci Biotechnol Biochem, 2009. 73(4): p. 817-21.

32. Kawada, S., et al., Cystine and theanine supplementation restores high-intensity resistance exercise-induced attenuation of natural killer cell activity in well-trained men. J Strength Cond Res, 2010. 24(3): p. 846-51.

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Stem Cell 100 - Powerful Rejuvenation and Anti-Aging ...

At a microscopic level, we are all composed of cells. Look at yourself in a mirror -- what you see is about 10 trillion cells divided into about 200 different types. Our muscles are made of muscle cells, our livers of liver cells, and there are even very specialized types of cells that make the enamel for our teeth or the clear lenses in our eyes!

If you want to understand how your body works, you need to understand cells. Everything from reproduction to infections to repairing a broken bone happens down at the cellular level. If you want to understand new frontiers like biotechnology and genetic engineering, you need to understand cells as well.

Anyone who reads the paper or any of the scientific magazines (Scientific American, Discover, Popular Science) is aware that genes are BIG news these days. Here are some of the terms you commonly see:

Gene science and genetics are rapidly changing the face of medicine, agriculture and even the legal system!

In this article, we'll delve down to the molecular level to completely understand how cells work. We'll look at the simplest cells possible: bacteria cells. By understanding how bacteria work, you can understand the basic mechanisms of all of the cells in your body. This is a fascinating topic both because of its very personal nature and the fact that it makes these news stories so much clearer and easier to understand. Also, once you understand how cells work, you will be able to answer other related questions like these:

All of these questions have obvious answers once you understand how cells work -- so let's get started!

Original post:
How Cells Work | HowStuffWorks

Stem Cell 100 is designed to rejuvenate your body and slow the aging process to help you feel and function more like a young person. This can help you feel better, look younger and improve your health.

Most of the cells in your body lose function with age. Everyone has special cells called adult stem cells which are needed to repair damaged and old tissues, but adult stem cells themselves are also aging.

Until now there was not much you could do about it. Stem Cell 100 rejuvenates adult stem cells and their micro-environments with the proprietary SC100 formula. Stem Cell 100+ is a more powerful and faster acting version of the same nutraceutical.

Developed by experts in the anti-aging field, patent-pending Stem Cell 100 is the only supplement proven to double maximum lifespan of an animal model. No other product or therapy including caloric restriction even comes close.

Harness the Power of Your Own Stem Cells

Millions of people suffer from chronic conditions of aging and disease. Based on international scientific studies in many academic and industry laboratories, there is new hope that many of the conditions afflicting mankind can some day be cured or greatly improved using stem cell regenerative medicine.

Stem Cell 100 offers a way to receive some of the benefits of stem cell therapy today by improving the effectiveness of your own adult stem cells.

Stem Cell 100 Helps to Support:

The statements above have not been reviewed by the FDA. Stem Cell 100 is not a preventive or treatment for any disease.

Help Rejuvenate Your Body by Boosting Your Own Stem Cells

As a child, we are protected from the ravages of aging and can rapidly recover from injury or illness because of the ability of the young regenerative stem cells of children have a superior ability to repair and regenerate most damaged tissues.

As we age, our stem cell populations become depleted and/or slowly lose their capacity to repair. Moreover, the micro-environment (i.e. niches) around stem cells becomes less nurturing with age, so cell turnover and repair are further reduced. This natural progression occurs so slowly that we are barely aware of it, but we start to notice the body changes in our 20s, 30s, 40s, and especially after 50 years of age.

Stem Cell 100 helps adults regain their youthful regenerative potential by stabilizing stem cell function.

Stem Cell 100 works differently than other stem cell products on the market

You may have seen a number of products that are advertised as stimulating or enhancing the number of stem cells. Each person only has a limited number of stem cells so using them up faster may not be a good strategy. Stem Cell 100 is about improving the effectiveness and longevity of your stem cells as well as preserving the stem cell micro-environment. That should be the goal of any effective stem cell therapy and is what Stem Cell 100 is designed to do and what other stem cell products cannot do.

Stem Cell 100 Extends Drosophila (Fruit Fly) Lifespan

In extensive laboratory testing Stem Cell 100 greatly extended both the average and maximum lifespan of Drosophila fruit flies. The study (see Charts below) included three cages of Drosophila fruit flies that were treated with Stem Cell 100 (Cages T1 to T3) and three cages which were untreated controls (Cages C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females.

The experiment showed that median lifespan more than doubled with a 123% increase.

While fruit flies are not people they are more like us than you might think. Drosophila have a heart and circulatory system, and the most common cause of death is heart failure. Like humans and other mammals (e.g. mice), it is difficult to increase their lifespan significantly.

These observed results outperform every lifespan enhancing treatment ever tested including experiments using genetic modification and dietary restriction.

The longest living fruit fly receiving Stem Cell 100 lived 89 days compared to the longest living untreated control which lived 48 days. It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation, however, there were many others that lived almost as long so it was not just an aberation.

The oldest 5% of the treated fruit flies lived 77% longer than the oldest 5% of the control group. It is also important that the study showed an improved ability of the fruit flies to survive stress and illness at all ages not just during old age. Even after the first few days of the study there were already more of the

Stem Cell 100 treated fruit flies alive that survived youth than the control group of untreated fruit flies. For additional information about the study please go to our Longevity page.

SK, Santa Fe, New Mexico

I have been using Stem Cell 100 for about one year. Initially I noticed a boost in energy level, which now remains steady-hence not noticed I have experienced no adverse effects from taking this product. I heartily recommend Stem Cell 100 and plan to continue on it.*

Leslie

Stem Cell 100 has made a noticeable difference in me, including turning my gray hair back to its original color, which supposedly is impossible. The reversal of the gray hair to original color began a couple of months after starting the pill. After about 10 months, the gray hair is mostly gone. At the current rate of improvement, I expect my hair to completely be back to its original color within 1 to 2 months. I think my beard will take longer, but it was the first to gray.

Also, my skin became smoother and younger looking. The skin and hair rely heavily on stem cells, and they seem to benefit strongly from this product. Im so excited about telling people my results because there is nothing that can reverse the graying of hair. It will give me evidence that this supplement thing is really powerful.

Unfortunately, I dont have before and after pictures because I didnt read any claims that the product would affect hair color. I would just say that Im a person who totally believes that it does me no good to imagine things or interpret tings in a way favorable to what I want to believe. When Im convinced enough to make a statement, you can count on it.*

Joey, California

I am a 48 year old working woman. A friend of mine introduced me to Stem Cell 100. After taking Stem Cell 100 for about 4 months my anxiety level has really been diminished. Its a great supplement and I would recommend it to everyone!*

Paul, California

I am an active 61 year old man in excellent health, but had experienced a serious drop in my energy level at the time I enrolled in a 4-month trial of Stem Cell 100. Within a month, my energy increased noticeably and I began to take to my physical activities (running, cycling) with a renewed enthusiasm and intensity level. My mood began to elevate steadily, and soon I had even lost those few stubborn pounds that had eluded me for years. I am very enthusiastic about Stem Cell 100. I look forward to continuing with the new, improved formulation, and would not hesitate to recommend it.*

Mike, Texas

After taking the Stem Cell 100 for the last month my sinuses have also cleared, unplugging my ears for the first time since mid September.*

Tom, Australia

Only after about 2-3 weeks of taking Stem Cell 100 my eye sight returned back to a level where I did not need glasses to work on my computer monitors. My eyes had always been good but had started to deteriorate about a year ago where 50% of the time I had to wear my glasses. I was shocked to find the improvement so quick. I found I was less stressed. No other changes to lifestyle yet a measureable difference.

My fingers would sometimes get stiff in the mornings after long days on the keyboard. This stiffness disappeared. Some of my hair is getting darker. I have a full body of hair that had virtually all turned grey but I noticed that some of my hair was starting regrow brown my original colour. I had some age spots in my left leg that are disappearing. Generally, I feel great.*

Willie, California

As I was sprinting this morning around 6:00am I noticed that I was not hurting anymore! I have been having sore knees, ankles, hamstrings and back for the last couple of years. I usually just ran through it, but I noticed since I have been taking the Stem Cell 100 capsules for about 45 days now, those nagging pains are gone away!*

*DIsclaimer: The testimonials reflect the real life experiences written and voluntarily submitted to us by individuals who used our products. Individual results may vary. We do not claim that any individual experience recounted is typical or representative of what any other consumer might experience.

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Supplement Facts

Stem Cell 100 and Stem Cell 100+ are Patent-Pending Life Code Nutraceuticals.

All Life Code products arenutraceutical grade and provide the best of science along with the balance of nature. Stem Cell 100+ is vegetarian.

Serving Size: One type O capsule

Servings Per Container: 60 Capsules

Recommended Use: Typical usage of Stem Cell 100 or Stem Cell 100+ is two capsules per day, preferably at meal times. While both capsules can be taken at the same time, it is preferable to separate the two capsules by at least 4 hours. Since Stem Cell 100 is a potent formulation, do not take more than three capsules per day. One capsule per day may be sufficient for those below 110 pounds.

Recommended Users: Anyone from ages 22 and up could benefit from Stem Cell 100 or Stem Cell 100+. Those in their 20s and 30s will like the boost in endurance during sports or exercise, while older users will notice better energy and general health with the potential for some weight loss.

Stem Cell 100 was our first multi-pathway longevity nutraceutical. Stem Cell 100+ is a more advanced, faster acting and powerful version of Stem Cell 100.

Click label to enlarge

Active Stem Cell 100 Ingredients: There are ten herbal components that make up the patent-pending combination in Stem Cell 100. The herbal components are highly extracted natural herbs that are standardized for active components that promote adult stem cells and lower inflammation:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems.

2) Proprietary natural blueberry flavonoids and other compounds from a stabilized pharmaceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which greatly reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury.

5) Pterocarpus Marsupium, which contains two stable resveratrol analogs which promote stem cells, lower inflammation, and stabilized metabolism.

6) Polygonum Multiflorium stem stem is a popular Chinese herbal tonic that fights premature aging and promotes youthfulness. Polygonum is reported to enhance fertility by improving sperm count in men and egg vitality in women. Polygonum is also widely used in Asia to strengthen muscle and is thus used by many athletes as an essential tonic for providing strength and stamina to the body.

Modern research has supported Polygonum multiflorium stem in that animal studies have proven that it can extend lifespan and improve the quality of life. Polygonum appears to protect the liver and brain against damage, perhaps by improving immune and cardiovascular health. The stem sections of Polygonum multiflorium are also calming to the nervous system and promote sounder sleep. Life Code uses a proprietary Polygonum multiflorium stem extract.

7) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In Chinese traditional medicine, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep.

Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Modern research indicates that Schisandra berry extracts have a protective effect on the liver and promote immunity. A double-blind human trial suggested that Schisandra berry may help patients with viral hepatitis, which is very prevalent in China.

Recent work indicates that the liver is protected by the enhanced production of glutathione peroxidase, which helps detoxify the liver. Life Code uses a proprietary Schisandra berry extract.

8) Fo-Ti Root (aka He-Shou-Wu) is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. Fo-Ti is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor.

Legend has it that Professor Li Chung Yun took daily doses of Fo-Ti to live to be 256 and is said to have outlived 23 wives and spawned 11 generations of descendents before his death in 1933. While it is unlikely that he really lived to such an old age there is scientific support for Fo-Ti as beneficial for health and longevity.

Like the Indian Keno bark, Fo-ti contains resveratrol analogs and likely acts by various mechanism, which includes liver detoxification and protection of skin from UVB radiation. Life Code uses a proprietary Fo-Ti root extract.

9) Camellia sinensis has many bioactive polyphenols including the potent epigallocatechin-3-gallate (EGCG). A 2006 Japanese study published in the Journal of the American Medical Association reports that adults aged 40 to 79 years of age who drank an average of 5 or more cups of tea per day had a significantly lower risk of dying from all causes (23% lower for females and 12% lower for males). The study tracked more than 40,000 adults for up to 11 years and found dramatically lower rates of cardiovascular disease and strokes in those drinking 5 or more cups of tea.

Many studies have found that adults drinking 3 or more cups of tea per day have significantly less cancer. Other studies have found that green tea helps protect against age-related cognitive decline, kidney disease, periodontal disease, and type 2 diabetes. Green tea also promotes visceral fat loss and higher endurance levels.

Summarizing all of the thousands of studies on tea and tea polyphenols that have been published, it can be concluded that tea polyphenols preserve health and youth. This conclusion is backed up by gene studies showing that tea polyphenols decrease insulin-like growth factor-1 (IGF-1), which is a highly conserved genetic pathway that has been strongly linked to aging in yeast, worms, mice, and humans. If everyone could drink 4 to 5 cups of green tea each day, they could enjoy these important health benefits, but for most people drinking that much green tea can disturb their sleep patterns.

Life Code uses a nutraceutical grade green tea extract that has 98% polyphenols and 50% ESCG that provides the polyphenol and ESCG equivalent of 4 to 5 cups of green tea with only 2% of the caffeine. Thus, most or all of the benefits of green tea are provided without concerns about disturbing sleep.

10) Drynaria Rhizome is used extensively in traditional Chinese medicine as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures.

Drynaria has also helped in many cases of bleeding gums and tinnitus (ringing in the ears). The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary Drynaria rhizome extract.

Safety: The extracts in both versions of Stem Cell 100 are pharmaceutical grade and have been individually tested in both animals and humans without significant safety issues. Those with pre-existing conditions of diabetes or hypertension should coordinate this product with your doctor, as lower blood glucose or reduced blood pressure can result from taking the recommended dose of this product.

Warnings: may lower glucose and/or blood pressure in some individuals. The supplement is not recommended for pregnant, lactating, or hypoglycemic individuals.

References

1. Yu, Q., Y.S. Bai, and J. Lin, [Effect of astragalus injection combined with mesenchymal stem cells transplantation for repairing the Spinal cord injury in rats]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2010. 30(4): p. 393-7.

2. Xu, C.J., et al., [Effect of astragalus polysaccharides on the proliferation and ultrastructure of dog bone marrow stem cells induced into osteoblasts in vitro]. Hua Xi Kou Qiang Yi Xue Za Zhi, 2007. 25(5): p. 432-6.

3. Xu, C.J., et al., [Effects of astragalus polysaccharides-chitosan/polylactic acid scaffolds and bone marrow stem cells on repairing supra-alveolar periodontal defects in dogs]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006. 31(4): p. 512-7.

4. Zhu, X. and B. Zhu, [Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice]. Hua Xi Yi Ke Da Xue Xue Bao, 2001. 32(4): p. 590-2.

5. Qiu, L.H., X.J. Xie, and B.Q. Zhang, Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull, 2010. 33(4): p. 641-6.

6. Araghi-Niknam, M., et al., Pine bark extract reduces platelet aggregation. Integr Med, 2000. 2(2): p. 73-77.

7. Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002. 40(4): p. 158-68.

8. Koch, R., Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res, 2002. 16 Suppl 1: p. S1-5.

9. Rimando, A.M., et al., Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem, 2005. 53(9): p. 3403-7.

10. Manickam, M., et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod, 1997. 60(6): p. 609-10.

11. Grover, J.K., V. Vats, and S.S. Yadav, Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab, 2005. 7(4): p. 414-20.

12. Mao, X.Q., et al., Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model. Acta Pharmacol Sin, 2007. 28(12): p. 1947-56.

13. Schafer, A. and P. Hogger, Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007. 77(1): p. 41-6.

14. Kwak, C.J., et al., Antihypertensive effect of French maritime pine bark extract (Flavangenol): possible involvement of endothelial nitric oxide-dependent vasorelaxation. J Hypertens, 2009. 27(1): p. 92-101.

15. Xue, B., et al., Effect of total flavonoid fraction of Astragalus complanatus R.Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine, 2008.

16. Mizuno, C.S., et al., Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARalpha. Bioorg Med Chem, 2008. 16(7): p. 3800-8.

17. Sato, M., et al., Dietary pine bark extract reduces atherosclerotic lesion development in male ApoE-deficient mice by lowering the serum cholesterol level. Biosci Biotechnol Biochem, 2009. 73(6): p. 1314-7.

18. Kimura, Y. and M. Sumiyoshi, French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless Mice. Photochem Photobiol, 2010.

19. Pavlou, P., et al., In-vivo data on the influence of tobacco smoke and UV light on murine skin. Toxicol Ind Health, 2009. 25(4-5): p. 231-9.

20. Ni, Z., Y. Mu, and O. Gulati, Treatment of melasma with Pycnogenol. Phytother Res, 2002. 16(6): p. 567-71.

21. Bito, T., et al., Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression. Free Radic Biol Med, 2000. 28(2): p. 219-27.

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Stem Cell 100 Longevity Telomere Support Supplement SC100 ...

Source: http://www.abc57.com By: Vahid Sadrzadeh

Video Link Here: ABC57 News See the Difference Michiana

An unprecedented stem cell procedure was performed today at a veterinary clinic in Michiana. [Click link above to watch video].

The surgery was for5-year-old German Shepherd, Nike, and set anexample of how stem cell therapy is changing modern medicine.

Although it took merely 30 minutes, it was toughfor Jayne Stommel to watch,Nikes owner and trainer.

Stommel traveled from Indianapolis to South Bend hoping the operation would relieve her 5-year-old super dog of arthritic pain and ensure Nike could continue working for many more years.

Stommelslove for training rescue dogs began long before Guinness and Nike came along.

After seeing the devastation of 9/11 firsthand, Stommel says shediscovered her calling.

With a little bit of research and the right dog,that dream became a reality.

Nike, is one of only 150 certified FEMA trained rescue dogs in the nation that actively works to find survivors of fires, building collapses and natural disasters.

While training at only a year old, Nike was in an accident which ultimately led to arthritis in her hips.

Nike is mid-career, she just turned five. If she doesnt have to stop because the pain in her hips, she should be able to go another four or five years, saidStommel.

Stommel knew in order to prolong Nikes career as long as possible, the stem cell procedure, which was affordable and minimally invasive, was necessary.

It takes a lot of work and training and thats after you find the right dog. They are very unique dogs. Being able to keep her working longer, is very important, saidStommel.

Noticing that Nike was favoring her hip during recent training, Stommelwas recommended to and then sought the help of Dr. Chris Persing and the team at Western Veterinary Clinic on the edge of South Bend.

The treatment was divided into two operations, the first was this morning.

We opened up her abdomen; we found a good healthy layer of fat that we pulled out. I handed that over to a staff so that she could prepare that tissue. To extrude the stem cells, to incubate them, to excite them, to get them ready for a job to do. Later on in the day, we went ahead and used those stem cells to inject in to Nikes hips, says Persing, Associate Veterinarian.

The injection went well and hopes are high for a full recovery.

After a two or three week period, she should be pretty much back to her normal activity and doing the things that she needs to for training again, saidPersing.

And in just two monthsStommels other German Shepherd, Guinness, will be joining that exclusive list of certified FEMA trained rescue K9s.

Until then the two train together, waiting for Nike to join the pack again.

Link:
Stem Cell Worx News

The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

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Epidermal stem cells of the skin. - National Center for ...

1. Introduction

Bone marrow is a complex tissue containing hematopoietic cell progenitors and their progeny integrated within a connective-tissue network of mesenchymal-derived cells known as the stroma (1). The stroma cells, or Mesenchymal stem cells (MSCs), are multi-potent progenitor cells that constitute a minute proportion of the bone marrow, represented as a rare population of cells that makes up 0.001 to 0.01% of the total nucleated cells. They represent 10-fold less abundance than the haematopoietic stem cells (2), which contributes to the organization of the microenvironment supporting the differentiation of hematopoietic cells (3). MSC are present in tissues of young, as well as, adult individuals (4, 5), including the adipose tissue, umbilical cord blood, amniotic fluid and even peripheral blood (1, 6-8). MSCs were characterized over thirty years ago as fibroblast-like cells with adhesive properties in culture (9, 10). The term MSC has become the predominant term in the literature since the early 90s (11), after which their research field has grown rapidly due to the promising therapeutic potential, resulting in an increased frequency of clinical trials in the new millennium at an explosive rate.

As data accumulated, there was a need to establish a consensus on the proper definition of the MSCs. The International Society for Cellular Therapy has recommended the minimum criteria for defining multi-potent human MSCs (12, 13). The criteria included: (i) cells being adherent to plastic under standard culture conditions; (ii) MSC being positive for the expression of CD105, CD73 and CD90 and negative for expression of the haematopoietic cell surface markers CD34, CD45, CD11a, CD19 or CD79a, CD14 or CD11b and histocompatibility locus antigen (HLA)-DR; (iii) under a specific stimulus, MSC differentiate into osteocytes, adipocytes and chondrocytes in vitro. These criteria presented properties to purify MSC and to enable their expansion by several-fold in-vitro, without losing their differentiation capacity. When plated at low density, MSCs form small colonies, called colony-forming units of fibroblasts (CFU-f), and which correspond to the progenitors that can differentiate into one of the mesenchymal cell lineages (14, 15). It has been reported lately that MSCs are able to differentiate into both mesenchymal, as well as, non-mesenchymal cell lineages, such as adipocytes, osteoblasts, chondrocytes, tenocytes, skeletal myocytes, neurones and cells of the visceral mesoderm, both in vitro and in vivo (16, 17).

All cells have half-lives and their natural expiration must be matched by their replacement; MSCs, by proliferating and differentiating, can be the proposed source of these new replacement cells as characterized in their differentiation capacity. This replacement hypothesis mimics the known sequence of events involved in the turnover and maintenance of blood cells that are formed from haematopoietic stem cells (HSCs) (18). Unlike HSCs, MSCs can be culture-expanded ex vivo in up to 40 or 50 cell doublings without differentiation (19). A dramatic decrease in MSC per nucleated marrow cell can be observed when the results are grouped by decade, thus showing a 100-fold decrease from birth to old age. Being pericytes present in all vascularized tissues, the local availability of MSC decreases substantially as the vascular density decreases by one or two orders of magnitude with age (20). In recent years, the discovery of MSCs with properties similar, but not identical, to BM-MSCs has been demonstrated in the stromal fraction of the connective tissue from several organs, including adipose tissue, trabecular bone, derma, liver and muscle (21-24). It is important to note that the origin of MSCs might determine their fate and functional characteristics (25). Studies of human bone marrow have revealed that about one-third of the MSC clones are able to acquire phenotypes of pre-adipocytes, osteocytes and chondrocytes (16). This is in concordance with data showing that 30% of the clones from bone marrow have been found to exhibit a trilineage differentiation potential, whereas the remainder display a bi-lineage (osteo-chondro) or uni-lineage (osteo) potential (26). Moreover, MSC populations derived from adipose tissue and derma present a heterogeneous differentiation potential; indeed, only 1.4% of single cells obtained from adipose-derived adult stem cell (ADAS) populations were tri-potent, the others being bi-potent or unipotent (27).

Mesenchymal Stem Cells have been shown to possess immunomodulatory characteristics, as described through the inhibition of T-cell proliferation in vitro (28-30). These observations have triggered a huge interest in the immunomodulatory effects of MSCs. The in vitro studies have been complemented in vivo, where both confirmed the immunosuppressive effect of MSC. MSC activating stimuli in vitro, appears to include the secretion of cytokines and the interaction with other immune cells in the presence of proinflammatory cytokines (Fig 1) (31). Primarily, the in vivo effect has been originally shown in a baboon model, in which infusion of ex vivoexpanded matched donor or third-party MSCs delayed the time to rejection of histo-incompatible skin grafts (29). The delay indicated a potential role for MSC in the prevention and treatment of graft-versus-host disease (GVHD) in ASCT, in organ transplantation to prevent rejection, and in autoimmune disorders. Recently, MSCs were used to successfully treat a 9-year-old boy with severe treatment-resistant acute GVHD, further confirming the potent immunosuppressive effect in humans (32). The immunosuppressive potential has no immunologic restriction, whether the MSCs are autologous with the stimulatory or the responder lymphocytes or the MSCs are derived from a third party. The degree of MSC suppression is dose dependent, where high doses of MSC are inhibitory, whereas low doses enhance lymphocyte proliferation in MLCs (33). Broadly, MSC modulate cytokine production by the dendritic and T cell subsets DC/Th1 and DC/Th2 (34), block the antigen presenting cell (APC) maturation and activation (35), and increase the proportion of CD4+CD25+ regulatory cells in a mixed lymphocyte reaction (36).

Potential mechanisms of the MSC interactions with immune cells. Mesenchymal stem cells (MSCs) can inhibit both the proliferation and cytotoxicity of resting natural killer (NK) cells, as well as, their cytokine production by releasing prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO) and soluble HLA-G5 (sHLA-G5). Killing of MSCs by cytokine-activated NK cells involves the engagement of cell-surface receptors (Thick blue line) expressed by NK cells with its ligands expressed on MSCs. MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), bias mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increase interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE2 is involved in all of these effects. Immature DCs are susceptible to activated NK cell-mediated lysis. MSC Direct inhibition of CD4+ T-cell function depends on their release of several soluble molecules, including PGE2, IDO, transforming growth factor-1 (TGF1), hepatocyte growth factor (HGF), inducible nitric-oxide synthase (iNOS) and haem-oxygenase-1 (HO1). MSC inhibition of CD8+ T-cell cytotoxicity and the differentiation of regulatory T cells mediated directly by MSCs are related to the release of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the increased generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function seems to depend on soluble factors and cellcell contact. Finally, MSCs dampen the respiratory burst and delay the spontaneous apoptosis of neutrophils by constitutively releasing IL-6.

Dendritic cells have the elementary role of antigen presentation to nave T cells upon maturation, which in turn induce the proinflammatory cytokines. Immature DCs acquire the expression of co-stimulatory molecules and upregulate expression of MHC-I and II, as well as, other cell-surface markers (CD11c and CD83). Mesenchymal stem cells have profound effect on the development of DC, where in the presence of MSC, the percentage of DC with conventional phenotype is reduced, while that of plasmacytoid DC is increased, therefore biasing the immune system toward Th2 and away from Th1 responses in a PGE-2 dependent mechanism (37). Furthermore, MSCs inhibit the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation (38). When mature DCs are incubated with MSCs they have a decreased cell-surface expression of MHC class II molecules, CD11c, CD83 and co-stimulatory molecules, as well as, decreased interleukin-12 (Il-12) production, thereby impairing the antigen-presenting function of the DCs (Fig 1) (39, 40). MSCs can also decrease the pro-inflammatory potential of DCs by inhibiting their production of tumour-necrosis factor (TNF-) (40). Furthermore, plasmacytoid DCs (pDCs), which are specialized cells for the production of high levels of type-I IFN in response to microbial stimuli, upregulate production of the anti-inflammatory cytokine IL-10 after incubation with MSCs (34). These observations indicate a potent anti-inflammatory and immunoregulatory effect for MSC in vitro and potentially in vivo.

Natural killer (NK) cells are key effector cells of the innate immunity in anti-viral and anti-tumor immune responses through their Granzyme B mediated cytotoxicity and the production of pro-inflammatory cytokines (41). NK-mediated target cell lysis results from an antigen-ligand interaction realized by activating NK-cell receptors, and associated with reduced or absent MHC-I expression by the target cell (42). MSCs can inhibit the cytotoxic activity of resting NK cells by down-regulating expression of NKp30 and natural-killer group 2, member D (NKG2D), which are activating receptors involved in NK-cell activation and target-cell killing (Fig 1) (43). Resting NK cells proliferate and acquire strong cytotoxic activity when cultured with IL-2 or IL-15, but when incubated with MSC in the presence of these cytokines, resting NK-cell, as well as, pre-activated NK cell proliferation and IFN- production are almost completely abrogated (44, 45). It is worth noting that although the susceptibility of NK cells to MSC mediated inhibition is potent, the pre-activated NK cells showed more resistance to the immunosuppressive effect of MSC compared to resting NK cells (43). The susceptibility of human MSCs to NK-cell-mediated cytotoxicity depends on the low level of cell-surface expression of MHC class I molecules by MSCs and the expression of several ligands, that are recognized by activating NK-cell receptors. Autologous and allogeneic MSC were susceptible to lysis by NK cells (43), where NK cell-mediated lysis was inversely correlated with the expression of HLA class I on MSC (46). Incubation of MSCs with IFN- partially protected them from NK-cell-mediated cytotoxicity, through the up-regulation of expression of MHC-I molecules on MSCs (43). Taken together, a possible dynamic interaction between NK cells and MSC in vivo exists, where the latter partially inhibit activated MSC, without compromising their ability to kill MSC, reflecting on an interaction tightly regulated by IFN- concentration.

Neutrophils play a major role in innate immunity during the course of bacterial infections, where they are activated to kill foreign infectious agents and accordingly undergo a respiratory burst. MSCs have been shown to dampen the respiratory burst and to delay the spontaneous apoptosis of resting and activated neutrophils through an IL-6-dependent mechanism (47). MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a (47). Stimulation with bacterial endotoxin induces chemokine receptor expression and mobility of MSCs, which secrete large amounts of inflammatory cytokines and recruit neutrophils in an IL-8 and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS, which suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet (48). Furthermore, MSC have shown the capability to mediate the preservation of resting neutrophils, a phenomenon that might be important in those anatomical sites, where large numbers of mature and functional neutrophils are stored, such as the bone marrow and lungs (49).

T-cells are major players of the adaptive immune response. After T-cell receptor (TCR) engagement, T cells proliferate and undergo numerous effector functions, including cytokine release and, in the case of CD8+ T cells (CTL), cytotoxicity. Abundant reports have shown that T-cell proliferation stimulated with polyclonal mitogens, allogeneic cells or specific antigen is inhibited by MSCs (28, 29, 50-56). The observation that MSCs can reduce T cell proliferation in vitro is mirrored by the in vivo finding through infusions of hMSCs that control GVHD following bone marrow transplantation. Nevertheless, there is no demonstrable correlation between the measured effects of MSCs in vitro and their counter effect in vivo due to the lack of universality of methodology correlating the in vitro findings with the in vivo therapeutic potential.

MSC inhibition of T-cell proliferation is not MHC restricted, since it can be mediated by both autologous and allogeneic MSCs and depends on the arrest of T-cells in the G0/G1 phase of the cell cycle (55, 57). Thus, MSCs do not promote T-cell apoptosis, but instead maintain T cell survival upon subjection to overstimulation through the TCR and upon commitment to undergo CD95CD95-ligand-dependent activation-induced cell death (57). MSC effects on T cell proliferation in vitro appear to have both contact-dependent and contact-independent components (58). Inhibition of T-cell proliferation by MSCs leads to decreased IFN- secretion in vitro and in vivo associated with increased IL-4 production by T helper 2 (TH2) cells (34, 59). Taken together, there is an implication for a shift from a pro-inflammatory state characterized by IFN- secretion to an anti-inflammatory state characterized by IL-4 secretion (Fig 1). An imperative role for effector T-cell is the MHC restricted killing of virally-infected or of allogeneic cells mediated via CD8+ CTLs, and which is down-regulated by MSC (60).

Regulatory T cells (Tregs), a subpopulation of T cells, are vital to keep the immune system in check, help avoid immune-mediated pathology and contain unrestricted expansion of effector T-cell populations, which results in maintaining homeostasis and tolerance to self antigens. Tregs are currently identified by co-expression of CD4 and CD25, expression of the transcription factor FoxP3, production of regulatory cytokines IL-10 and TGF-, and ability to suppress proliferation of activated CD4+CD25+ T cells in co-culture experiments. Differential expression of CD127 (-chain of the IL-7 receptor) enable flow cytometry-based separation of human Tregs from CD127+ non-regulatory T-cells (61). MSCs have been reported to induce the production of IL-10 by pDCs, which, in turn, trigger the generation of regulatory T cells (Fig 1) (34, 40). Furthermore, Tregs secrete TGF- and when used in vitro, TGF- in combination with IL-2 directs the differentiation of T-cells into Tregs, while Tregs suppress the proliferation of TCR-dependent proliferation of effector CD25null or CD25low T-cells in a non-autologous fashion. Also TGF- alters angiogenesis following injury in experiments using MSC (62). In addition, after co-culture with antigen-specific T-cells, MSCs can directly induce the proliferation of regulatory T-cells through release of the immunomodulatory HLA-G isoform HLA-G5 (Fig 1) (63). Taken together, MSCs can modulate the intensity of an immune response by inhibiting antigen-specific T-cell proliferation and cytotoxicity and promoting the generation of regulatory T-cells.

Antibody producing B-cells constitute the second main cell type involved in adaptive immunity. Interactions between MSCs and B-cells have produced controversial results attributable to the inconsistent experimental conditions used (31, 55, 64). Initial reports on mice suggested that MSC exercise a dampening effect on the proliferation of B-cells (64), which is in concordance with most published works to date (31, 55, 64). Furthermore, MSCs can also inhibit B-cell differentiation and constitutive expression of chemokine receptors via the release of soluble factors and cell-cell contact mediated possibly by the Programmed Cell Death 1 (PD-1) and its ligand (31, 64). The addition of MSCs, at the beginning of a mixed lymphocyte reaction (MLC), considerably inhibited immunoglobulin production in standard MLC, irrespective of the MSC dose employed, which suggests that third-party MSC are able to suppress allo-specific antibody production, consequently, overcoming a positive cross-match in sensitized transplant recipients (65). However, other in vitro studies have shown that MSCs could support the survival, proliferation and differentiation to antibody-secreting cells of B-cells from normal individuals and from pediatric patients with systemic lupus erythematosus (66, 67). A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments, where hMSCs inhibited B-cell differentiation shown as significant impairment of IgM, IgG, and IgA production. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B-cells (Fig 1). B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs (64). Regardless of the controversial in vitro effects, B-cell response is mainly a T-cell dependent mechanism, and thus its outcome is significantly influenced by the MSC-mediated inhibition of T-cell functions. More recently, Corcione et al have shown that systemic administration of MSCs to mice affected by experimental autoimmune encephalomyelitis (EAE), a prototypical disease mediated by self-reactive T cells, results in striking disease amelioration mediated by the induction of peripheral tolerance (52). In addition, it has been shown that tolerance induction by MSCs may occur also through the inhibition of dendritic-cell maturation and function (34, 35), thus suggesting that activated T cells are not the only targets of MSCs.

Low concentrations of IFN- upregulate the expression of MHC-II molecules by MSCs, which indicates that they could act as antigen presenting cells (APCs) early in an immune response, when the level of IFN- are low (68, 69). However, this process of MHC-II expression by MSCs, along with the potential APC characteristics, was reversed as IFN- concentrations increased. These observations could suggest that MSCs function as conditional APC in the early phase of an immune response, while later switch into an immunosuppressive function (68). Since bone marrow might be a site for the induction of T-cell responses to blood-borne antigens (70), and since MSC are derived from the stromal progenitor cells that reside in the bone marrow, therefore, MSC express a yet unidentified role in the control of the immune response physiology of the bone marrow. Dendritic cells are the main APC for T-cell responses, and MSC-mediated suppression of DC maturation would prohibit efficient antigen presentation and thus, the clonal expansion of T-cells. Direct interactions of MSCs with T-cells in vivo could lead to the arrest of T-cell proliferation, inhibition of CTL-mediated cytotoxicity and generation of CD4+ regulatory T-cells. As a consequence, impaired CD4+ T-cell activation would translate into defective T-cell help for B-cell proliferation and differentiation to antibody-secreting cells.

The hMSCs express few to none of the B7-1/B7-2 (CD80/CD86) costimulatorytype molecules; this appears to contribute, at least in part, to their immune privilege characteristic. Mechanisms that lead to immune tolerance rely on interrelated pathways that involve complex cross talk and cross regulation of T-cells and APCs by one another. Both soluble mediators and modulation exerted via complex networks of cytokines and costimulatory molecules appear to play a role in MSC regulation of T cells, and these mechanisms invoke both contact-dependent and -independent pathways.

Although many of the studies use MSC-conditioned medium, both contact-dependent and -independent mechanisms are probably invoked in the therapeutic use of MSCs (20, 71). In addition to cytokines, the network of costimulatory molecules is hypothesized to play a prominent role in modulating tolerance and inflammation. MSCs down-regulate the expression of costimulatory molecules (30, 72, 73). The discovery of new functions for B7 family members, together with the identification of additional B7 and CD28 family members, is revealing new ways in which the B7:CD28 family may regulate T-cell activation and tolerance. Not only do CD80/86:CD28 interactions promote initial T-cell activation, they also regulate self-tolerance by supporting CD4+CD25+ Treg homeostasis (74-76). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can exert inhibitory effects in both B7-1/B7-2dependent and independent fashions. B7-1 and B7-2 can signal bi-directionally through engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells (77). The B7 family membersinducible co-stimulator (ICOS) ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1)are expressed on professional APC cells, while B7-H4 and B7-H1 are expressed on hMSCs and on cells within non-lymphoid organs. These observations may provide a new means for regulating T-cell activation and tolerance in peripheral tissues (31, 71, 78). ICOS and PD-1 are expressed upon T-cell-induction, and they regulate previously activated T-cells (79). Both the ICOS:ICOSL pathway and the PD-1:PD-L1/PD-L2 pathway play a critical role in regulating T-cell activation and tolerance (79). There is consensus that both CTLA-4 and PD-1 inhibit T-cell and B-cell activation and may play a crucial role in peripheral tolerance (79, 80). Both CTLA-4 and PD-1 functions are associated with Rheumatoid Arthritis (RA) and other autoimmune diseases. PD-1 is over expressed on CD4+ T cells in the synovial fluid of RA patients (81). Whether or not these costimulatory molecules are critical mediators of MSC-mediated immune suppression and/or tolerance in vivo is still under current investigation.

Studies have shown that MSCs escape the immune system, and this makes them a potential therapeutic tool for various transplantation procedures. MSCs express intermediate levels of HLA major histocompatibility complex (MHC) class I molecules (16, 50, 82, 83), while they do not express HLA class II antigens of the cell surface. However, HLA class II is readily detectable by Western blot on whole-cell lysates of unstimulated adult MSCs, thus suggesting that MSCs contain intracellular deposits of HLA class II allo-antigens (83). Cell-surface expression can be induced by treatment of the cells with IFN- for 1 or 2 days. Unlike adult MSCs, the fetal liver derived cells have no intracellular nor cell surface HLA class II expression (84), but incubation with IFN- initiated their intracellular expression followed by surface expression. Differentiation of MSCs into their mesodermal lineages of bone, cartilage, or adipose tissue, both in adult and fetal MSCs continued to express HLA-I, but not class II (84). Undifferentiated MSCs in vitro fail to elicit a proliferative response from allogeneic lymphocytes, thus suggesting that the cells are not inherently immunogenic (28, 30, 50). When pre-cultured with IFN- for full HLA class II expression, MSCs still escape recognition by allo-reactive T-cells, (83, 84) as is the case with MSCs differentiated adipocytes, osteoblasts, and chondrocytes. Limited in vivo data demonstrate the persistence of allogeneic MSCs into immunocompetent hosts after transplantation. In one patient treated with MSCs, DNA of donor MSC could not be detected in any organ at autopsy few weeks after the infusion, while in another patient receiving MSCs from two donors, the donor DNA from both donors was detected in lymph node and colon, the target organs of GVHD, within weeks after infusion (85). Data from our lab indicated that MSC were undetectable after two weeks in an allogeneic system (86). Therefore, the question of whether MSCs are recognized by an intact allogeneic immune system in vivo remains open, although the in vitro data support the theory that MSCs escape the immune system. MSCs do not express FAS ligand or costimulatory molecules, such as B7-1, B7-2, CD40, or CD40L (50). When costimulation is inadequate, T-cell proliferation can be induced by the addition of exogenous costimulation. However, MSCs differ from other cell types, and no T-cell proliferation can be observed when they are cultured with HLA-mismatched lymphocytes in the presence of a CD28-stimulating antibody (50). However, in agreement with the in vitro data, infusion or implantation of allogeneic and MHC-mismatched MSCs into baboons has been well tolerated (87-89). Unique immunologic properties of MSCs were also suggested by the fact that engraftment of human MSCs occurred after intra-uterine transplantation into sheep, even when the transplantation was performed after the fetuses became immunocompetent (90). MSC mainly fail to activate T-cells and show to be targets for CD8+ T cell-cytotoxicity, althought controversial (60). Phyto-hemagglutinin (PHA) blasts, generated to react against a specific donor, will lyse chromium-labeled mononuclear cells from that individual but it will not lyse MSCs derived from the same donor. Furthermore, killer cell inhibitory receptor (KIR ligand)mismatched natural killer cells do not lyse MSCs (60). Thus, MSCs, although incompatible at the MHC, tend to escape the immune system.

Although MSCs are transplantable across allogeneic barriers, a delayed type hypersensitivity reaction can lead to rejection in xenogenic models of human MSCs injected into immunocompetent rats (91). In this study, MSCs were identified in the heart muscle of severe compromised immune deficiency rats, in contrast to that of immunocompetent rats. In the latter group, peripheral blood lymphocytes proliferated after re-stimulation with human MSCs in vitro, thus suggesting cellular immunization. Such a proliferative response in vitro has not been detected in humans treated with intravenous (IV) infusion of allogeneic MSCs (Le Blanc and Ringdn, unpublished data, 2004).

Several studies have acknowledged the immunosuppressive activities of MSCs, but the underlying mechanisms are far from being fully characterized. The initial step in the interaction between MSCs and their target cells involves cellcell contact mediated by adhesion molecules, in concordance with studies showing the dependence of T-cell proliferation on the engagement of PD-1 by its ligand (31). Several soluble immunosuppressive factors, either produced constitutively by MSCs or released following cross-talk with target cells have been reported, including nitric oxide and indoleamine 2,3-dioxygenase (IDO), which are only released by MSC after IFN- stimulation with target cells (92, 93), and thus not in a constitutive manner. IDO induces the depletion of tryptophan from the local environment, which is an essential amino acid for lymphocyte proliferation. MSC-derived IDO was reported as a requirement to inhibit the proliferation of IFN--producing TH1 cells (92) and together with prostaglandin E2 (PGE-2) to block NK-cell activity (Fig 1) (44). In addition, IFN-, alone or in combination with TNF-, IL-1 or IL-1, stimulates the production of chemokines by mouse MSCs that attract T-cells and stimulate the production of inducible nitric-oxide synthase (iNOS), which in turn inhibits T-cell activation through the production of nitric oxide (56). It is worth noting that MSCs from IFN- receptor (IFN--R1) deficient mice do not have immunosuppressive activity, which highlights the vital role of IFN- in the immunosuppressive function of MSC (56).

Additional soluble factors, such as transforming growth factor-1 (TGF-1), hepatocyte growth factor (HGF), IL-10, PGE-2, haem-oxygenase-1 (HO1), IL-6 and soluble HLA-G5, are constitutively produced by MSCs (28, 34, 51, 63, 94) or secreted in response to cytokines released by target cells upon interacting with MSC. TNF- and IFN- have been shown to stimulate the production of PGE-2 by MSCs above constitutive level (34). Furthermore, IL-6 was shown to dampen the respiratory burst and to delay the apoptosis of human neutrophils by inducing phosphorylation of the transcription factor signal transducer and activator of transcription 3 (47), and to inhibit the differentiation of bone-marrow progenitor cells into DCs (95).

The failure to reverse suppression, when neutralizing antibodies against IL-10, TGF- and IGF were added to MLR reactions does point to the possibility that MSC may secrete as yet uncharacterized immunosuppressive factors (93). Galectin-1 and Galectin-3, newly characterized lectins, are constitutively expressed and secreted by human bone marrow MSC. Inhibition of galectin-1 and galectin-3 gene expression with small interfering RNAs abrogated the suppressive effect of MSC on allogeneic T-cells (Fig 1) (96). The restoration of T-cell proliferation in the presence of - lactose indicates that the carbohydrate-recognition domain of galectins is responsible for the immunosuppression of T-cells and highlights an extracellular mechanism of action for the MSC-secreted galectins. In this respect, the inhibition of T-cell proliferation could result from either direct effects of galectin-1 and galectin-3 on T cells and/or through a direct or an indirect on effect on dendritic cells (97).

HLA-G5 represents another important molecule involved in MSC mediated regulation of the immune response, where its production has been shown to suppress T-cell proliferation, as well as NK-cell and T-cell cytotoxicity, while promoting the generation of Tregs (63, 98). HLA-G protein expression is constitutive and the level is not modified upon stimulation by allogeneic lymphocytes in MSC/MLR. HLA-G5 is detected on MSCs by real-time reverse-phase polymerase chain reaction, immune-fluorescence, flow cytometry and enzyme-linked immunosorbent assay in the supernatant (99). Cell contact between MSCs and activated T-cells induces IL-10 production, which, in turn, stimulates the release of soluble HLA-G5 by MSCs (63). It is worth nothing that none of these molecules have an exclusive role and that MSC-mediated immune-regulation is a redundant system that is mediated by several molecules.

One important characteristic of hMSCs is their ability to suppress inflammation resulting from injury, as well as, resulting from allogeneic solid organ transplants, and autoimmune disease. Consistent with in vitro studies, murine allogeneic MSCs are effective cellular therapy models in the treatment of murine models of human disease (52, 100-102). Several studies have documented the substantial clinical improvements observed in animal models, when MSC were systemically introduced as a therapy in mouse models of multiple sclerosis (102, 103), inflammatory bowel disease (104-106), infarct, stroke, and other neurologic diseases (107, 108), as well as diabetes (109). These findings strongly suggest that xenogeneic hMSCs are not immunologically recognized by various immunocompetent mouse models of disease and are able to home to sites of inflammation. However, the mechanisms behind the immunosuppressive actions at the site of inflammation and its association with the homing activity have not yet been completely elucidated.

Nitric Oxide (NO) mediate its effect partly through phosphorylation of Stat-5, which results in suppression of T- cell proliferation, partly through the inhibition of NO synthase or the inhibition of prostaglandin synthesis. This reveals the MSC-dependent effects on proliferation. Although indoleamine-2, 3-dioxygenase (IDO) has been hypothesized to be critical in mediating the effect of NO, neutralizing IDO by using a blocking antibody did not interfere with NOs suppressive effects (93, 110).

Within an in vivo setting, injury, inflammation, and/or foreign cells can lead to T-cell activation, which results in those T-cells producing proinflammatory cytokines including, but not limited to, TNF-, IFN-, IL-1, and IL-1. Combinations of cytokines may also induce cell production of chemokines, some of which bind to CXCR3-R expressing cells (including T cells) that co-localize with MSCs. MSCs then produce NO, which inhibits Stat-5 phosphorylation, thereby leading to cell-cycle arrest (and thus halting T cell proliferation) (Fig 1) (110). In addition, iNOS appears to be important in mouse MSC in vivo effects. MSCs from mice that lack iNOS (or IFN-R1) are unable to suppress GVHD. In contrast to mouse MSCs that use NO in mediating their immune-suppressive effect, hMSCs and MSCs from non-human primates appear to mediate their immune-suppressive effects via IDO (56). There is some controversy about whether the effect of IDO results from local depletion of tryptophan, or from the accumulation of tryptophan metabolites (which is suggested by data showing that use of a tryptophan antagonist, 1-methyl-L tryptophan, restored allo-reactivity that would otherwise have been suppressed by MSCs). In addition to its effect on the JAK-STAT pathway, NO may also influence mitogen activated protein kinase and nuclear factor B, which would cause a reduction in the gene expression of proinflammatory cytokines.

The clinical experience with and the safety of MSCs is of utmost interest for their wide therapeutic applications. The pioneering in vivo studies with MSC focused on the engraftment facilitation for the haematopoietic stem cells (111). Further work also focused on the regenerative functions of MSC in terms of functional repair of damaged tissues (112). Hypoimmunogenicity of MSC provided a critical advantage in their use for clinical and therapeutic purposes in vitro (50), followed by pre-clinical studies (29) and reaching the human clinical studies (32) with the use of allogeneic donors. Allogeneic MSC have proved to be an option with major advantages in clinical use, since the use of autologous MSC is hindered by the limited time frame for clonal expansion and the costly in vitro proliferation. However, some sub-acute conditions, such as autoimmune diseases, might allow the use of autologous MSCs and their culture in vitro. It is worth noting that some reports have recently challenged the belief that allogeneic MSCs are poorly immunogenic (113, 114), indicating that in some cases an autologous MSC source could be advantageous. Recent reports have shown that MSCs from patients with autoimmune disease have a normal capability to support hematopoiesis, (115) and to exercise immunomodulatory functions (116), and to show a normal phenotypic characteristics (117).

The perspective role of adult stem cells in degenerative disease conditions, where there is progressive tissue damage and an inability to repair, possibly due to the depletion of stem cell populations or functional alteration, has been considered. In cases of osteoarthritis, a disease of the joints where there is progressive and irreversible loss of cartilage characterized by changes in the underlying bone, Murphy et al showed that the proliferative capacity of the MSC was substantially reduced, and this was independent of the harvest site from patients with end-stage OA undergoing joint replacement surgery (118). In this study the marrow samples were harvested both from the site of surgery (either the hip or the knee) and also from the iliac crest. These effects were apparently disease-related, and not age-related. However, the data suggest that susceptibility to OA and perhaps other degenerative diseases may be due to the reduced mobilization or proliferation of stem cells. In addition, successfully recruited cells may have a limited capacity to differentiate, leading to defective tissue repair. Alternatively, the altered stem cell activity may be in response to the elevated levels of inflammatory cytokines seen in OA, which was confirmed by several other investigators (119, 120).

Similarly, the functional impairment of the anti-proliferative effect of MSCs derived from patients with aplastic anaemia (121) or multiple myeloma (122) might be resulting from an intrinsic abnormality in the microenvironment of the bone marrow, which is consistent with the possible use of autologous MSC for therapeutic purposes.

With the knowledge of the homing capacity of MSC and their capacity to engraft into the recipients bone after systemic administration, MSCs have been utilized to treat children with severe osteogenesis imperfecta, leading to improved parameters of increased growth velocity and total body mineral content associated with fewer fractures (123). Systemic infusion of allogeneic MSCs also led to encouraging bone marrow recovery in patients with tumors following chemotherapy (123). The immunosuppressive effect of infused MSCs has been successfully shown in acute, severe graft-versus-host disease (GvHD) (32). The probable effect of MSC was the inhibition of donor T-cell reactivity to histocompatibility antigens of the recipient tissue. Currently, there is no successful therapy for steroid-refractory acute GVHD. The possible role of MSCs in this context is therefore of potential interest. Le Blanc et al reported a case of grade IV acute GVHD of the gut and liver in a patient who had undergone ASCT with cells from an unrelated female donor (32). The patient was unresponsive to all types of immunosuppression drugs. When the patient was infused with 2x 106 MSCs per kilogram from his HLA-haploidentical mother, his GVHD responded with a decline in bilirubin and normalization of stools. After the MSC infusion, DNA analysis of his bone marrow showed the presence of minimal residual disease (124). When immunosuppression was discontinued, the patient again developed severe acute GVHD, with its associated symptoms within a few weeks.

Modulation of host allo-reactivity led to accelerated bone-marrow recovery in patients co-transplanted with MSCs and haplo-identical HSCs (125). Clinical trials are being conducted on the immunomodulatory potential of MSCs in the treatment of Crohns disease, with the potential for those cells to contribute to the regeneration of gastrointestinal epithelial cells (126).

As described previously, MSCs are characterized by their hypoimmunogenicity. In 2000, data from several research groups demonstrated long-term allo-MSC engraftment in a variety of non-cardiac tissues in the absence of immunosuppression (88, 90). On the basis of these observations, investigators began to look into the possibility of allo-MSCs engraftment into affected myocardium in rats, and later in swine, where allo-MSCs were found to readily engraft in necrotic myocardium and favorably alter ventricular function (2). The allo-MSC engraftment occurred without evidence of immunologic rejection or lymphocytic infiltration in the absence of assisted immunosuppressive therapy emphasizing some of the apparent advantages of these cells over other cell populations for cellular cardiomyoplasty. The immunologically privileged status of MSCs was also observed in xenogeneic setting, where Saito et al injected MSC intravenously from C57BL/6 mice into immunocompetent adult Lewis rats (127). When these animals were later subjected to MIs, murine MSCs could be identified in the region of necrosis, and these cells expressed muscle specific proteins not present before coronary ligation.

Consistent with results from in vitro studies, murine allogeneic MSCs are effective in the treatment of murine models of human disease (52, 103, 128). Several studies have reported clinical improvements in mouse models of multiple sclerosis and amyotrophic lateral sclerosis, inflammatory bowel disease, stroke, diabetes, infarct and GVHD using I.V. injected xenogeneic hMSCs rather than allogeneic MSCs (108, 109). A major advantage in using hMSCs in mouse models of human disease is that the possibility of gathering mechanistic data through measuring biomarkers from body fluids or using noninvasive imaging technology, which may prove to be an advantage in clinical studies when applied on humans.

In experiments designed to study the trafficking of hMSCs, investigators used mouse models of severe erosive polyarthritis characterized by an altered transgene allele that results in chronic over-expression of TNF- and which resemble human RA patients (60, 72). The motive behind utilizing these mice models was to investigate similarities in MSC homing with mouse models of chronic asthma and acute lung injury. Injected hMSC revealed a reduction in ankle arthritis parameters associated with decrease appendage related erythema, possibly due to the MSC localization to ankle joints as revealed by bioluminescence (129). Similar observations for inducing tolerance were made using adipose-derived MSC, where Treg were induced in RA PBMC and in mouse models of arthritis (36, 130). Furthermore, studies of rheumatoid arthritis T-cells showed a down-regulation of effector response using adipose-derived MSCs (131). Variations in this potential described by the capability of MSCs to down-regulate collagen-induced arthritis, and in the ability to induce Tregs, depend on the source of MSC (mouse vs. human) and its characteristics (primary isolate of MSC line), which reflect on difference in function compared to primary expanded MSC (132). Other studies reported that in the collagen-induced model of arthritis, mice infused with MSCs have increased numbers of CD4+CD25+ cells that express FoxP3 and thus reveal a Treg phenotype (20). Recent data on collagen-induced arthritis model, where murine MSCs did not reveal therapeutic benefits against arthritis in vivo, but did show anti-proliferative effect in vitro suggest that there is no appropriate in vitro measures that can be accurately extrapolated into a potential therapeutic utility of MSCs in vivo, and that mouse MSCs show difference in functional characteristics to hMSC in terms of immunoregulatory capacity (133).

MSCs immunological properties appeared to have potential therapeutic advantages in other forms of autoimmune diseases, especially in type 1 diabetes. In NOD mouse model, several physiological defects that aim to maintain peripheral and central tolerance contribute to the development of autoimmune diabetes. These defects are summed up as a combination of immune cell dysfunction (including T-cell, NK cells, B-cells, and dendritic cells), associated with the presence of inflammatory cytokine milieu (134). MSCs possess specific immunomodulatory properties capable of halting autoimmunity through immunomodulation processes described in this chapter. The processes might be through a direct effect via the presentation of differential levels of negative costimulatory molecules and the secretion of regulatory cytokines that affect regulatory T-cells/autoreactive T-cells. Furthermore, MSCs could modulate the immunological dysregulation observed in antibody producing B-cells and cytotoxic NK cells. Dendritic cells have been shown to be defective in NOD mice characterized by higher levels of costimulation with a potential capability to shift to a TH-1 type of immune response.

In an experimental mouse model of diabetes induced by streptozotocin, it was observed that MSCs promoted the endogenous repair of pancreatic islets and renal glomeruli (109). Similarly, co-infusion of MSCs and bone-marrow cells inhibited the proliferation of -cell-specific T-cells isolated from the pancreas of diabetic mice and restored insulin and glucose levels through the induction of recipient-derived pancreatic -cell regeneration in the absence of trans-differentiation of MSCs (135). These studies show that the in vivo administration of MSCs is clinically efficacious through the modulation of pathogenic - and T-cell responses and through potent bystander effects on the target tissue.

The timing of MSC infusion seems to be a critical parameter in their therapeutic efficacy. In the EAE mouse model of multiple sclerosis, MSC systematically injected at disease onset ameliorated myelin oligodendrocyte glycoprotein (MOG)-induced EAE and further decreased the infiltration T-cells, B-cells and macrophages into the central nervous system (CNS). Furthermore, T cells isolated from the lymph nodes of MSC-treated mice did not proliferate after in vitro re-challenge with MOG peptide, which is an indication of the induction of T-cell anergy (52). Systematic injection of MSCs was found to inhibit the in vivo production of pathogenic plp-specific antibodies and to suppress the encephalitogenic potential of plp-specific T cells in passive-transfer experiments. In this model, the MSCs migrated to the lymphoid organs, as well as, to the inflamed CNS, where they exercised a protective effect on the neuronal axons in situ (135, 136). In these studies, the therapeutic effect of MSCs depended on the release of anti-apoptotic, anti-inflammatory and trophic molecules, as occurred in the case of stroke in rats (137), and, possibly, on the recruitment of local progenitors and their subsequent induction to differentiate into neural cells (138). As trophic effect, the MSCs appeared to favor oligo-dendrogenisis by neural precursor cells (139).

Several other studies have provided insights into the effects of MSCs mediated by cytokines. In a model of acute renal failure, the administration of MSCs increased the recovery of renal function through the inhibition of production of proinflammatory cytokines, such as Il-1, TNF and IFN, and through an anti-apoptotic effect on target cells (140). Along the same line, the anti-inflammatory activity of MSCs was revealed in a mouse model of lung fibrosis, where they inhibited the effects of IL-1-producing T cells and TNF-producing macrophages through the release of IL-1 receptor antagonist (IL-1RA) (141). The release of trophic factors such as the WNT-associated molecule secreted frizzled-related protein 2 (SFRp2), which leads to the rescue of ischemic cardiomyocytes and the restoration of ventricular functions represent another important function for MSC (142).

With all the promising therapeutic potential of MSC, there seems to be a growing concern about their association with tumors. The immunoregulatory and anti-proliferative effects of MSCs led to several studies investigating the inhibitory effect of MSCs on tumor growth. Inhibition or, more frequently, stimulation of tumor-cell proliferation in vitro and/or tumor growth in vivo by MSCs has been reported (143-145). The heterogeneous nature of the MSC populations and the different experimental tumor models used, contribute to the effect of tumors on MSC in which the microenvironment generated by tumors influence the behavior of MSCs (146). Two main mechanisms are probably involved in the enhancement of tumor growth by MSCs. First, the cell-to-cell cross-talk between MSCs and tumor cells contribute to tumor progression, thus integrating within the tumor stroma (147), and second, the suppressive effects of MSCs on the immune system of tumor-bearing hosts might facilitate tumorigenesis, as shown for the inhibition of melanoma rejection, possibly mediated by regulatory CD8+ T cells (144). Irrespective of the possible interactions between cancer cells, immune cells and MSCs, the potential risk of stimulating the growth cancer by MSCs must be considered.

As a whole, the data accumulated from preclinical and clinical data indicate that bone marrow-derived MSCs have, in addition to their therapeutic purposes in regenerative medicine, effects that can result from other characteristics, such as their anti-proliferative and anti-inflammatory properties. The immuno suppressive activity of MSCs provides means for inducing peripheral tolerance following systemic injection mediated through the inhibition of cell division, thereby preventing their responsiveness to antigenic triggers while maintaining them in a quiescent state. In addition, the clinical efficacy of MSCs in different experimental model seems to occur almost only during the acute phase of disease associated with limited trans-differentiation, which indicates that the therapeutic effectiveness of MSCs relies heavily on their ability to modify microenvironments. These modifications occur through the release of anti-inflammatory cytokines, and anti-apoptotic and trophic molecules that promote the repair and protection of damaged tissues, as well as, maintain the integrity of the immune cells.

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Mesenchymal Stem Cells: Immunology and Therapeutic ...

Conference Series LLCinvites all the participants from all over the world to attend '8th World Congress on Cell & Stem Cell Research during March 20-22, 2017 in Orlando, USA which includes prompt keynote presentations, Oral talks, Poster presentations and Exhibitions.

Stem cellsare cells originate in all multi-cellular organisms. They were isolated in mice in 1981 and in humans in 1998. In humans there are several types of stem cells, each with variable levels of potency. Stem cell treatments are a type of cell therapy that introduces new cells into adult bodies for possible treatment of cancer, diabetes, neurological disorders and other medical conditions. Stem cells have been used to repair tissue damaged by disease or age.

Objective

Stem Cell Research-2017 has the platform to fulfill the prevailing gaps in the transformation of this science of hope, to serve promptly with solutions to all in the need. Stem Cell Research 2017 will have an anticipated participation of 120+ delegates across the world to discuss the conference goal.

Success Story: Cell Science Conference Series

The success of the Cell Science conference series has given us the prospect to bring the gathering inOrlando,USA. Since its commencement in 2011 Cell Science series has witnessed around 750 researchers of great potentials and outstanding research presentations from around the world. Awareness of stem cells and its application is becoming popular among the general population. Parallel offers of hope add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

About Organizers

Conference Series LLCis one of the leadingOpen Access publishersand organizers of international scientificconferences and events every year across USA, Europe & Asia Conference Series LLChas so far organized 3000+Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business with 700+ peer-reviewed open accessjournalsin basic science, health, and technology. OMICS International is also in association with more than 1000 International scientific and technological societies and associations and a team of 30,000 eminent scholars, reputed scientists as editorial board members.

Scientific Sessions

Stem Cell Research-2017 will encompass recent researches and findings in stem cell technologies, stem cell therapies and transplantations, current understanding of cell plasticity in cancer and other advancements in stem cell research and cell science.Stem Cell Research-2017 will be a great platform for research scientists and young researchers to share their current findings in this field of applied science. The major scientific sessions in Stem Cell Research-2017will focus on the latest and exciting innovations in prominent areas of cell science and stem cell research.

Target Audience:

Eminent personalities, Directors, CEO, President, Vice-president, Organizations, Associations heads and Professors, Research scientists, Stem Cell laboratory heads, Post-docs, Students other affiliates related to the area of Stem cell research, stem cell line companies can be as Target Audience.

8th World Congress on Cell & Stem Cell Research

The success of the 7 Cell Science conferences series has given us the prospect to bring the gathering one more time for our 8thWorld Congress 2017 meet in Orlando, USA. Since its commencement in 2011 cell science series has perceived around 750 researchers of great potentials and outstanding research presentations around the globe. The awareness of stem cells and its application is increasing among the general population that also in parallel offers hope and add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

Stem Cell Research-2017has the goal to fill the prevailing gaps in the transformation of this science of hope to promptly serve solutions to all in the need.World Congress 2017 will have an anticipated participation of 100-120 delegates from around the world to discuss the conference goal.

History of Stem cells Research

Stem cells have an interesting history, in the mid-1800s it was revealed that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Efforts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the capacity to generate blood cells. In 1968, the first bone marrow transplant was achieved successfully to treat two siblings with severe combined immunodeficiency. Other significant events in stem cell research include:

1978: Stem cells were discovered in human cord blood 1981: First in vitro stem cell line developed from mice 1988: Embryonic stem cell lines created from a hamster 1995: First embryonic stem cell line derived from a primate 1997: Cloned lamb from stem cells 1997: Leukaemia origin found as haematopoietic stem cell, indicating possible proof of cancer stem cells

Funding in USA:

No federal law forever did embargo stem cell research in the United States, but only placed restrictions on funding and use, under Congress's power to spend. By executive order on March 9, 2009, President Barack Obama removed certain restrictions on federal funding for research involving new lines of humanembryonic stem cells. Prior to President Obama's executive order, federal funding was limited to non-embryonic stem cell research and embryonic stem cell research based uponembryonic stem celllines in existence prior to August 9, 2001. In 2011, a United States District Court "threw out a lawsuit that challenged the use of federal funds for embryonic stem cell research.

Members Associated with Stem Cell Research:

Discussion on Development, Regeneration, and Stem Cell Biology takes an interdisciplinary approach to understanding the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex fully patterned adult organism, as well as the intimately related question of how adult structures regenerate. Stem cells play critical roles both during embryonic development and in later renewal and repair. More than 65 faculties in Philadelphia from both basic science and clinical departments in the Division of Biological Sciences belong to Development, Regeneration, and Stem Cell Biology. Their research uses traditional model species including nematode worms, fruit-flies, Arabidopsis, zebrafish, amphibians, chick and mouse as well as non-traditional model systems such as lampreys and cephalopods. Areas of research focus include stem cell biology, regeneration, developmental genetics, and cellular basis of development, developmental neurobiology, and evo-devo (Evolutionary developmental biology).

Stem Cell Market Value:

Worldwide many companies are developing and marketing specialized cell culture media, cell separation products, instruments and other reagents for life sciences research. We are providing a unique platform for the discussions between academia and business.

Global Tissue Engineering & Cell Therapy Market, By Region, 2009 2018

$Million

Why to attend???

Stem Cell Research-2017 could be an outstanding event that brings along a novel and International mixture of researchers, doctors, leading universities and stem cell analysis establishments creating the conference an ideal platform to share knowledge, adoptive collaborations across trade and world, and assess rising technologies across the world. World-renowned speakers, the most recent techniques, tactics, and the newest updates in cell science fields are assurances of this conference.

A Unique Opportunity for Advertisers and Sponsors at this International event:

http://stemcell.omicsgroup.com/sponsors.php

UAS Major Universities which deals with Stem Cell Research

University of Washington/Hutchinson Cancer Center

Oregon Stem Cell Center

University of California Davis

University of California San Francisco

University of California Berkeley

Stanford University

Mayo Clinic

Major Stem Cell Organization Worldwide:

Norwegian Center for Stem Cell Research

France I-stem

Stem Cell & Regenerative Medicine Ctr, Beijing

Stem Cell Research Centre, Korea

NSW Stem Cell Network

Monash University of Stem Cell Labs

Australian Stem Cell Centre

Target Audience:

Eminent personalities, Directors, CEO, President, Vice-president, Organizations, Associations heads and Professors, Research scientists, Stem Cell laboratory heads, Post-docs, Students other affiliates related to the area of Stem cell research, stem cell line companies can be as Target Audience

Market Analysis of Stem Cell Therapy:

The global market for stem cell products was $3.8 billion in 2011. This market is expected to reach nearly $4.3 billion in 2012 and $6.6 billion by 2016, increasing at a compound annual growth rate (CAGR) of 11.7% from 2011 to 2016.

Americas is the largest region of global stem cell market, with a market share of about $2.0 billion in 2013. The region is projected to increase to nearly $3.9 billion by 2018, with a CAGR of 13.9% for the period of 2013 to 2018

Europe is the second largest segment of the global stem cell market and is expected to grow at a CAGR of 13.4% reaching about $2.4 billion by 2018 from nearly $1.4 billion in 2013.

Figure 2:Global Market

Companies working for Stem Cells:

Company

Location

Business Type

Cynata Therapeutics

Armadale, Australia

Stem Cell Manufacturing Technology

Mesoblast

Melbourne, Australia

Regenerative Medicine

Activartis

Vienna, Austria

Dendritic Cell-Based Cancer Immunotherapy

Aposcience

Vienna, Austria

Treatments composed of mixture of cytokines, growth factors and other active components

Cardio3 Biosciences

Mont-Saint-Guibert, Belgium

Stem Cell Differentiation

Orthocyte (BioTime)

Alameda, CA

Cellular Therapies

Capricor

Beverly Hills, CA

Stem Cell Heart Treatments

Life Stem Genetics

Beverly Hills, CA

Autologous stem cell therapy

International Stem Cell

Carlsbad, CA

Proprietary Stem Cell Induction

Targazyme

Carlsbad, CA

Cell Therapy

DaVinci Biosciences

Costa Mesa, CA

Cellular Therapies

Invitrx Therapeutics

Irvine, CA

Autologous Stem Cell Therapy, Therapeutic & Cosmetic

Stem Cell Softwares :

Products Manufactured By Industry Related to Stem Cell:

Excerpt from:
Worlds leading Stem Cell Conference | Global Meetings ...

Embryonic stem cells, as their name suggests, are derived from embryos. Most embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitroin an in vitro fertilization clinicand then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body.

Growing cells in the laboratory is known as cell culture. Human embryonic stem cells (hESCs) aregenerated by transferringcells from a preimplantation-stage embryointo a plastic laboratory culture dish that contains a nutrient broth known as culture medium. The cells divide and spread over the surface of the dish. In the original protocol, the inner surface of the culture dish was coated with mouse embryonic skin cellsspecially treated so they will not divide. This coating layer of cells is called a feeder layer. The mouse cells in the bottom of the culture dish provide the cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Researchers have nowdevised ways to grow embryonic stem cells without mouse feeder cells. This is a significant scientific advance because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.

The process of generating an embryonic stem cell line is somewhat inefficient, so lines are not produced each time cells from the preimplantation-stage embryo are placed into a culture dish. However, if the plated cells survive, divide and multiply enough to crowd the dish, they are removed gently and plated into several fresh culture dishes. The process of re-plating or subculturing the cells is repeated many times and for many months. Each cycle of subculturing the cells is referred to as a passage. Once the cell line is established, the original cells yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line. At any stage in the process, batches of cells can be frozen and shipped to other laboratories for further culture and experimentation.

At various points during the process of generating embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them embryonic stem cells. This process is called characterization.

Scientists who study human embryonic stem cells have not yet agreed on a standard battery of tests that measure the cells' fundamental properties. However, laboratories that grow human embryonic stem cell lines use several kinds of tests, including:

As long as the embryonic stem cells in culture are grown under appropriate conditions, they can remain undifferentiated (unspecialized). But if cells are allowed to clump together to form embryoid bodies, they begin to differentiate spontaneously. They can form muscle cells, nerve cells, and many other cell types. Although spontaneous differentiation is a good indication that a culture of embryonic stem cells is healthy, the process is uncontrolled and therefore an inefficient strategy to produce cultures of specific cell types.

So, to generate cultures of specific types of differentiated cellsheart muscle cells, blood cells, or nerve cells, for examplescientists try to control the differentiation of embryonic stem cells. They change the chemical composition of the culture medium, alter the surface of the culture dish, or modify the cells by inserting specific genes. Through years of experimentation, scientists have established some basic protocols or "recipes" for the directed differentiation of embryonic stem cells into some specific cell types (Figure 1). (For additional examples of directed differentiation of embryonic stem cells, refer to the 2006 NIH stem cell report.)

Figure 1. Directed differentiation of mouse embryonic stem cells. Click here for larger image. ( 2008 Terese Winslow)

If scientists can reliably direct the differentiation of embryonic stem cells into specific cell types, they may be able to use the resulting, differentiated cells to treat certain diseases in the future. Diseases that might be treated by transplanting cells generated from human embryonic stem cells include diabetes, traumatic spinal cord injury, Duchenne's muscular dystrophy, heart disease, and vision and hearing loss.

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Excerpt from:
What are embryonic stem cells? [Stem Cell Information]