Archive for the ‘Skin Stem Cells’ Category
If we cut off the tail of a lizard, it grows back. If we cut off the hand of a human being, it does not grow back. Why not? This question has perplexed scientists for a long time. Recently scientists at the Translational Genomics Research Institute (TGen) and Arizona State University (ASU) in the US identified three tiny RNA switches (known as microRNAs) which turn genes on and off and are responsible for the regeneration of tails in the green lizard. Now researchers are hoping that using the next generation genomic DNA and computer analysis will lead to discoveries of new therapeutic approaches to switch on similar regenerative genes in human beings.
Micro RNAs are able to control many genes at the same time. They have been compared to an orchestra conductor controlling and directing many musicians. Hundreds of genes (musicians playing the orchestra of life), controlled by a few micro RNA switches, have been identified that are responsible in the regenerative process. This may well mark the beginning of a new era in which it may be possible to regenerate cartilage in knees, repair spinal cords and amputated limbs.
Tissue regeneration has become an attractive field of science, triggered by exciting advances in stem cell technologies. Stem cells are undifferentiated biological cells that are then converted into various types of cells such as heart, kidney or skin through a process known as differentiation. They can divide into more stem cells and provide a very effective mechanism for repair of damaged tissues in the body. The developing embryo contains stem cells which are then transformed into specialised cells as the embryo develops. They can be obtained by extraction from the bone marrow, adipose tissue or blood, particularly the blood from the umblical cord after birth.
Stem cells are now finding use in a growing number of therapies. For instance leukaemia is a cancer of the white blood cells. To treat leukaemia, one approach is to get rid of the diseased white blood cells and replace them with healthy cells. This may be done by a bone marrow transplant through which the patients bone marrow stem cells are replaced with those from a healthy, matching donor. If the transplant is successful, the stem cells migrate into the patients bone marrow resulting in the production of new, healthy white blood cells that replace the abnormal cells. Stem cells can now be artificially grown and then transformed (differentiated) into the heart, kidney, nerve or other typed of cells.
The field of regenerative medicine is developing at a fast pace. It involves the replacement, engineering or regeneration of human tissues and organs so that their normal function can be restored. Tissues and organs can also be grown in the laboratory if the body cannot heal itself. If the cells of the organ being grown are derived from the patients own cells, the possibility of rejection of the transplanted organ is minimised. Stem cells may also be used to regenerate organs.
Each year about 130,000 organs, mostly kidneys, are transplanted from one human being to another. The process of growing organs artificially has been greatly accelerated by the advent of 3D bioprinting. This involves the use of 3D printing technologies through which a human organ, liver or kidney, is produced by printing it with cells, layer-by-layer. This became possible when it was discovered that human cells can be sprayed through the nozzles of an inkjet printer without destroying or damaging them. Tissues and organs can thus be produced and transplanted into humans. Joints, jaw bones and ligaments can also be produced in this manner.
Initially, the work was confined to animals when ears, bones and muscle tissues were produced by bioprinting and then successfully transplanted into animals. Even prosthetic ovaries of mice were produced and transplanted so that the recipient mice could conceive and give birth later. While gonads have not been produced by bioprinting in humans, blood vessels have already been produced by the printing process and successfully transplanted into monkeys. Considerable work is also going on in the production of human knee cartilage pads through the bioprinting process. Wear and tear of the cartilage results in difficulties in walking, particular in older age groups, and often requires knee replacement through surgeries. The development of technologies to replace the damaged cartilages with new cartilages made by bioprinting could prove to be invaluable.
Another area of active research in this field is the production of human skin by bioprinting which may be used for treating burns and ulcers. Technologies have been developed to spray stem cells derived from the patient directly on the areas of the body where the skin is needed. In this way, stem cells help skin cells regrow under suitable conditions. Similar progress is being made in generating liver, kidney and heart tissues so that the long waiting time for donors can be circumvented.
When will we be able to print entire human organs? It has been estimated that complete human kidneys and livers should become commercially available through the bioprinting process within five to seven years. Hearts will probably take longer because of their more complex internal structure. However, one thing is clear: a huge revolution is now taking place in the field of regenerative medicine, triggered by spectacular advances in stem cell research. This presents a wonderful opportunity for learning and developing expertise in this field for us in our country.
In Pakistan a number of important steps have been taken in this fast evolving field. One of them is the establishment of a first rate facility for stem cell research in the Dr Panjwani Centre for Molecular Medicine and Drug Research (PCMD) in the University of Karachi. This institution has already earned an international reputation because of its outstanding publications in this field.
A second important development is that plans to set up an Institute for Translational Regenerative Medicine at PCMD so that Pakistan remains at the cutting edge in this fast emerging field are now under way.
Such initiatives can however only contribute to the process of socio-economic development if they operate under an ecosystem that is designed to promote the establishment of a strong knowledge economy.
Pakistan spends only about 0.3 percent of its GDP on science and about two percent of its GDP on education, bringing the nations ranking to the lowest 10 countries in the world. This is largely due to the stranglehold of the feudal system over our democracy. It is only by tapping into our real wealth our children that Pakistan can emerge from the quagmire of illiteracy and poverty and stand with dignity in the comity of nations.
The writer is chairman of UN ESCAP Committee on Science Technology & Innovation and former chairman of the HEC. Email: [emailprotected]
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Amazing medicine – The News International
Jonathan Pitre battles blood, lung infections before second stem cell transplant
People with RDEB have a fault in the gene responsible for a specific kind of collagen that connects the outer layer of skin, the epidermis, with those below it. The clinical trial seeks a biochemical correction to that fault. If the transplant works …
Stem cells are a rapidly advancing field of biological research. Since Dr. James Thomson first cultivated human embryonic stem cells at the University of Wisconsin – Madison in the late 1990s, this field of researched has exploded with potential. The links below provide access to a curriculum developed under the supervision of Dr. Thomson as well as the co-directors and staff of the UW Stem Cell & Regenerative Medicine Center. The material has been reviewed for accuracy by the scientists actually conducting the research and was compiled and formatted by Craig Kohn, a high school teacher with research experience, for a high school audience. The PowerPoint presentation works in conjunction with the notesheet, allowing for students to work independently if preferred. More information about specific instructional practices can be found below in Teacher Notes. PowerPoint: http://bit.ly/ted-stemcells Notesheet: http://bit.ly/ted-stemcellsnotesheet Quiz: http://bit.ly/ted-stemcellsquiz Additional resources about stem cells can be found at: http://www.stemcells.wisc.edu/node/386 http://stemcells.nih.gov/Pages/Default.aspxhttp://www.stemcellschool.org/http://www.nursingdegree.net/blog/750/25-best-blogs-for-following-stem-cell-research/
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What are stem cells? – Craig A. Kohn | TED-Ed
Adult stem cell function declines with age leading to the decline in fitness
The potential therapeutic use of stem cells is a very hot topic these days. Most of the attention has focused on embryonic stem cells and induced Pluripotent Stem cells (iPS cells), which can form every tissue type in the body to regenerate failing organs. The problem is that detailed knowledge is lacking for how to stimulate the embryonic stem cells to form differentiated tissues (e.g. cells that form the heart, pancreas, muscle, and brain). Moreover, because embryonic stem cells are unlimited in their ability to form any type of tissue, the risk of cancer looms large over the therapeutic use of embryonic stem cells. For example, both embryonic and IPS stem cells can form tumors called teratomas when injected into immune-compromised mice. Enter the bodys adult stem cells, which have not generally been associated with cancer and have been used safely as therapeutics in many countries. The problem with adult stem cells is that it is difficult to get enough of them to be effective for most indications or target the harvested adult stem cells to the proper tissue. Moreover, there are scores of different types of adult stem cells in the body, so picking the best type of adult stem cell for a particular therapeutic can be challenging. Thus, adult stem cell therapeutics with all its potential to regenerate damaged organs and tissues is still a work in progress.
But what about the many populations of endogenous adult stem cells that everyone has embedded in every organ system of the body? All the organs and differing tissues of the body appear to have adult stem cells available for regenerating cells in case of injury or disease. It was recently discovered that even brain neurons and heart muscle cells (previously thought to be non-dividing and irreplaceable in adults) have their own reservoirs of adult stem cells for regeneration. Unfortunately, as we age most adult stem cell populations either decline in number and/or lose the ability to differentiate into functional tissue-specific cells. For example, cardiac muscle stem cells exist but old folks have only one half the number of cardiac stem cells found in young people. Thus, adult stem cells become more and more dysfunction with age, which progressively increases organ and tissue dysfunction with age.
There are many examples revealing the role of adult stem cells in aging. First, the outer surface of your skin continuously sloughs off dead cells, so that adult stem cells must continuously replenish the dying skin cells to maintain the skin as an effective protective barrier to the outside world. With age, there are progressively fewer functional skin stem cells, so cell turnover in the skin slows, leading to thinner, dryer skin that loses its elasticity and youthful beauty. Second, hair also thins and goes grey, as functional follicle stem cell decline and the adult stem cells generating hair color also decline. Third, the differing adult stem cells that maintain the tissues composing skeletal muscle, pancreas, heart, bone, liver, kidney, and the immune system lose functional capacity, raising the potential for decline in tissue function or outright failure with age. As a final example, the five senses of sight, hearing, smell, taste, and touch slowly wane with age, as the declining stem cell populations responsible for maintaining these functions are unable to fully replenish the sensory neurons after injury and random cell death.
If your own adult stem cells are a key factor in aging and disease, then one novel way to slow aging and disease is to stimulate your own adult stem cells to maintain their proper numbers and functional capacity to differentiate into the various tissues as needed for repair and regeneration. This makes sense, because in most, if not all, organs of the body, old cells are continually being replaced by new cells coming from the adult stem cell populations. If stem cells are not producing enough new cells, then organs slowly decline in function as you age. Thus, stimulating your own stem cells can be a winning strategy to stave off many of the disorders associated with aging.
In practice, however, stimulating adult stem cell populations in the body is not a simple task. If the proliferation of adult stem cells is over stimulated, then one may get overgrowth of tissues or a potential tumor. Alternatively, one may stimulate the stem cells to proliferate in a balanced and regulated way, but the stem cells lose functionality and cannot differentiate into the desired specialized tissues to replace senescent cells. These twin problems promoting over stimulation or dysfunctional stem cells put real limits on any proposed therapeutic for stimulating stem cells. For example, most current treatments to stimulate immunity or stem cells (nave T cells) rely on complex carbohydrates from mushrooms or microorganisms to provide antigenic material that can stimulate immunity. This will activate the immune system stem cells to make more differentiated non-stem memory T cells directed against the antigenic material, but it does nothing to stimulate more immune stem cells (nave T cells). Indeed, chronic use of such stem cell enhancers may actually lead to stem cell depletion, as more adult stem cells are exhausted from the requirement to respond to the constant presence of the polysaccharide antigen. Indeed, one theory of how the HIV virus causes a defective immune system is that it exhausts the supply of nave T cells by the repeated attacks of the mutating HIV virus.
Stem Cell 100TM is a nutraceutical supplement that improves the function of your existing stem cells rather than over stimulate stem cells to differentiate or divide. By promoting the stability and vitality of adult stem cells they have the capacity to divide when the body signals a need for more stem cells and differentiated cells. When an organ or tissue is damaged, it will send out natural signals that new cells are needed to replace old or damaged cells. Stem Cell 100TM allows the adult stem cells to respond to the damage signal by provided new differentiated cells to replace the old damaged cells and also make more adult stem cells to keep up the stem cell population. Two other compounds in Stem Cell 100TM provide further natural support for stem cells.
(Note that not everyone will experience the same effects, as conditions vary among individuals. The general expectation is that for most health measurements that are in the Normal Range for your age, Stem Cell 100TM will promote readings that you had when some 20 years younger.)
The statements above have not been reviewed by the FDA. Stem Cell 100TM is not meant as a preventive or treatment for any disease.
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Stem Cells and Aging | Life Code
Stem cells collected from fat may have use in anti-aging treatments
Adult stem cells collected directly from human fat are more stable than other cells — such as fibroblasts from the skin — and have the potential for use in anti-aging treatments, according to researchers from the Perelman School of Medicine at the …
Human stem cells grown on Kyoto University’s “fiber-on-fiber” culturing system(Credit: Kyoto University)
Mighty promising as they are, stem cells certainly aren’t easy to come by. Recent scientific advances have however given their production a much-needed boost, with a Nobel-prize winning technology that turns skin cells into embryonic-like stem cells and another that promises salamander-like regenerative abilities being just a couple of examples. The latest breakthrough in the area comes from Japanese researchers who have developed a nanofiber matrix for culturing human stem cells, that they claim improves on current techniques.
The work focuses on human pluripotent stem cells (hPSCs), which have the ability to mature into any type of adult cell, be they those of the eyes, lungs or hair follicles. But that’s assuming they can be taken up successfully by the host. Working to improve the odds on this front, scientists have been exploring ways of culturing pluripotent stem cells in a way that mimics the physiological conditions of the human body, allowing them to grow in three dimensions rather than in two dimensions, as they would in a petrie dish.
Among this group is a team from Japan’s Kyoto University, which has developed a 3D culturing system it says outperforms the current technologies that can only produce low quantities of low-quality stem cells. The system consists of gelatin nanofibers on a synthetic mesh made from biodegradable polyglycolic acid, resulting in what the researchers describe as a “fiber-on-fiber” (FF) matrix.
The team found that seeding human embryonic stem cells onto this type of matrix saw them adhere well, and enabled an easy exchange of growth factors and supplements. This led to what the researchers describe as robust growth, with more than 95 percent of the cells growing and forming colonies after just four days of culture.
And by designing a special gas-permeable cell culture bag, the team also demonstrated how they could scale up the approach. This is because several of the cell-loaded matrices can be folded up and placed inside the bag, with testing showing that this approach yielded larger again numbers of cells. What’s more, the FF matrix could even prove useful in culturing other cell types.
“Our method offers an efficient way to expand hPSCs of high quality within a shorter term,” the team writes in its research paper. “Additionally, as nanofiber matrices are advantageous for culturing other adherent cells, including hPSC-derived differentiated cells, FF matrix might be applicable to the large-scale production of differentiated functional cells for various applications.”
The research was published in the journal Biomaterials.
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Nanofiber matrix sends stem cells sprawling in all directions – Gizmag – New Atlas
When most cells divide, they simply make more of themselves. But stem cells, which are responsible for repairing or makingnew tissue, have a choice: They can generate more stem cells or differentiate into skin cells, liver cells, or virtually any of the bodys specialized cell types.
As reported February 3 in Science, scientists at The Rockefeller University have discovered that this pivotal decision can hinge on whether or not tiny organ-like structures, organelles, are divvied up properly within the dividing stem cell.
In order for the bodys tissues to develop properly and maintain themselves, renewal and differentiation must be carefully balanced, says senior author Elaine Fuchs, the Rebecca C. Lancefield Professor and head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. Our experiments suggest an unexpected role for the positioning and inheritance of cellular organelles, in this case enzyme-filled peroxisomes, in controlling this intricate balance.
An uneven division
The outer section of the skin, the epidermis, provides a protective barrier for the body, and stem cells reside deep within it. During development, these cells divide so that one renewing stem cell daughter remains inward while the other daughter differentiates and moves outward to become part of the epidermis outer layers. First author Amma Asare, a graduate student in the lab, wanted to know how skin cells first emerge and begin this transition.
Looking in developing mouse skin, Asare devised an approach to identify genes that help guide the balance between new cells that either stay stem-like or differentiate. One particular protein, Pex11b, caught her attention. It is associated with the membrane that surrounds the peroxisome, an organelle that helps to free energy from food.
Asare showed that the protein seems to work by making sure the organelles are in the right locations so they can be divided between the daughter cells. In cells that lacked Pex11b, peroxisomes werent divvied up evenlyin some cases, one daughter cell ended up with all of the peroxisomes and the other didnt get any at all. And for those cells whose peroxisome distribution was disrupted, cell division took longer, and the mitotic spindle, the structure that separates the daughters genetic material, didnt align correctly.
The net result of depleting skin stem cells of Pex11b, Asare found, was that fewer daughter cells were able to differentiate into mature skin cells.
A delay changes fate
The researchers next moved peroxisomes around in the cell using a sophisticated laboratory technique, and the effect was the same. If the peroxisomes are in the wrong positions during cell division, no matter how they get there, that slows down the process, Asare says.
The effect for the whole organism was dramatic: If peroxisome positioning was disrupted in the stem cells, the mice embryos could no longer form normal skin.
While some evidence already suggested the distribution of organelles, including energy-producing mitochondria, can influence the outcome of cell division, we have shown for the first time that this phenomenon is essential to the proper behavior of stem cells and formation of the tissue, says Fuchs, who is also a Howard Hughes Medical Institute Investigator.
February 13, 2017 by Nicholas Weiler
Research led by scientists at UC San Francisco and Case Western Reserve University School of Medicine has used brain “organoids”tiny 3-D models of human organs that scientists grow in a dish to study diseaseto identify root causes of Miller-Dieker Syndrome (MDS), a rare genetic disorder that causes fatal brain malformations.
MDS is caused by a deletion of a section of human chromosome 17 containing genes important for neural development. The result is a brain whose outer layer, the neocortex, which is normally folded and furrowed to fit more brain into a limited skull, instead has a smooth appearance (lissencephaly) and is often smaller than normal (microcephaly). The disease is accompanied by severe seizures and intellectual disabilities, and few infants born with MDS survive beyond childhood.
In the new studypublished online January 19, 2017 in Cell Stem Cellthe research team transformed skin cells from MDS patients and normal adults into induced pluripotent stem cells (IPSCs) and then into neural stem cells, which they placed in a 3 dimensional culture system to grow organoid models of the human neocortex with and without the genetic defect that causes MDS.
Closely observing the development of these MDS organoids over time revealed that many neural stem cells die off at early stages of development, and others exhibit defects in cell movement and cell division. These findings could help explain how the genetics of MDS leads to lissencephaly, the authors say, while also offering valuable insights into normal brain development.
“The development of cortical organoid models is a breakthrough in researchers’ ability to study how human brain development can go awry, especially diseases such as MDS,” said Tony Wynshaw-Boris, MD, PhD, chair of the Department of Genetics and Genome Studies at Case Western Reserve University School of Medicine, and co-senior author of the new study. “This has allowed us to identify novel cellular factors that contribute to Miller-Dieker syndrome, which has not been modeled before.”
‘Smooth Brain’ Organoids Reveal Defects
Previous research on the causes of lissencephaly has relied on mouse models of the disease, which suggested that the main driver of the disorder was a defect in the ability of young neurons to migrate to the correct location in the brain. But Arnold Kriegstein, MD, PhD, professor of neurology, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and co-senior author, says there are significant drawbacks to this approach.
“Unlike the human brain, the mouse brain is naturally smooth,” Kriegstein said. “If you are studying a disease that leads to a smooth brain in humans, it’s a challenge to study it in an animal that normally has a smooth brain.”
The mouse brain also lacks a type of neural stem cell called outer radial glia, which were discovered by Kriegstein’s group in 2010. These cells are thought to have played a crucial role in the massive expansion in size and complexity of the primate brain relative to other mammals over the course of evolution.
In order to more accurately model the progression of MDS in the embryonic human brain, study first author Marina Bershteyn, PhD, a postdoctoral researcher in the Wynshaw-Boris and Kriegstein labs, spearheaded the development of MDS cortical organoids and techniques to observe how stem cells within these organoids developed in the laboratory into the different cell types seen in first-trimester embryonic human brains.
Bershteyn and her team found using time-lapse imaging that outer radial glia cells that grew in patient-derived organoids had a defect in their ability to dividepotentially contributing to the small, smooth brains seen in MDS patients.
“There are just fundamental differences in how mouse and human brains grow and develop,” said Bershteyn, who is now a scientist at Neurona Therapeutics, a company founded by Kriegstein and colleagues to develop stem cell therapies for neurological diseases. “Part of the explanation for why these observations were not made before is that outer radial glia cells are quite rare in mouse.”
In addition, the team found that early neural stem cells called neuroepithelial cells which are present in both mice and humans die at surprisingly high rates in MDS organoids, and when they do survive, divide in an abnormal wayas if they are prematurely transforming into neurons, cutting short important early stages of brain development.
Consistent with prior mouse studies, time-lapse imaging also revealed that newborn neurons are unable to migrate properly through developing brain tissue, which potentially contributes to the failure of MDS brains to properly form outer brain structures.
Organoid Research Opens Doors to Studying Human Brain Diseases in Lab
Together, these observations helped the team pinpoint developmental stages and specific neural cell types that are impaired in MDS. The next step to understanding lissencephaly more broadly, the authors say, will be to test cells from patients with different genetic forms of the disease, so researchers can begin to link specific mutations with the cellular defects that drive brain malformation.
The study is also a demonstration of the utility of patient-derived brain organoids as a way to bridge the gap between animal models and human disease, the authors say. In particular, the finding that human outer radial glia cells readily grow in organoid models opens the door for scientists worldwide to study the role of these cells in both normal human brain development and disease.
“Patient-derived cortical organoids are creating a huge amount of excitement,” Kriegstein said. “We are now able to study human brain development experimentally in the lab in ways that were not possible before.”
Explore further: Scientists engineer gene pathway to grow brain organoids with surface folding
More information: Marina Bershteyn et al. Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia, Cell Stem Cell (2017). DOI: 10.1016/j.stem.2016.12.007
One of the most significant ways in which the human brain is unique is the size and structure of the cerebral cortex. But what drives the growth of the human cortex, likely the foundation for our unique intellectual abilities?
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The human cerebral cortex contains 16 billion neurons, wired together into arcane, layered circuits responsible for everything from our ability to walk and talk to our sense of nostalgia and drive to dream of the future. …
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Walter and Eliza Hall Institute researchers have used advanced cellular, bioinformatics and imaging technology to reveal a long-lived type of stem cell in the breast that is responsible for the growth of the mammary glands …
Research led by scientists at UC San Francisco and Case Western Reserve University School of Medicine has used brain “organoids”tiny 3-D models of human organs that scientists grow in a dish to study diseaseto identify …
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When she was just 11 months old, Billie Sue Wozniaks daughter Juno was diagnosed with type 1 diabetes, an autoimmune disease that affects 1.25 million people and approximately 200,000 children under age 20 in the United States.
The disease had affected several members of Billie Sues family, including her uncle, who passed away at the age of 30.
My first thought was, Her life is going to be short, the 38-year-old from Reno, Nevada recalled. The more that I learned, the more I found that many people with type 1 live longer and the treatment advances are really exciting.
While looking for treatments, Wozniak learned about encapsulation therapy, in which an encapsulated device containing insulin-producing islet cells derived from stem cells is implanted under the skin. The encapsulation device is designed to protect the cells from an autoimmune attack and may help people produce their own insulin.
After learning of the therapy through JDRF, Wozniak saw an ad on Facebook for Store-A-Tooth, a company that offers dental stem cell banking. She decided to move forward with the stem cell banking, just in case the encapsulation device became an option for Juno.
In March 2016, a dentist extracted four of Junos teeth, and sent them to a lab so her stem cells could be cryopreserved. Wozniak plans to bank the stem cells from Junos molars as well.
Its a riskI dont know for sure if it will work out, Wozniak said.
Dental stem cells: a future of possibilities
For years, stem cells from umbilical cord blood and bone marrow have been used to treat blood and bone marrow diseases, blood cancers and metabolic and immune disorders.
Although there is the potential for dental stem cells to be used in the same way, researchers are only beginning to delve into the possibilities.
Dental stem cells are not science fiction, said Dr. Jade Miller, president of the American Academy of Pediatric Dentistry. I think at some point in time, were going to see dental stem cells used by dentistson a daily practice.
Dental stem cells have the potential to produce dental tissue, bone, cartilage and muscle. They may be used to repair cavities, fix a tooth damaged from periodontal disease or bone loss, or even grow a tooth instead of using dental implants.
In fact, stem cells can be used to repair cracks in teeth and cavities, according to a recent mouse study published in the journal Scientific Reports.
Theres also some evidence that dental stem cells can produce nerve tissue, which might eliminate the need for root canals. A recent study out of Tufts University found that a collagen-based biomaterial used to deliver stem cells to the inside of damaged teeth can regenerate dental pulp-like tissues.
Dental stem cells may even be able to treat neurological disorders, spinal cord and traumatic brain injuries.
I believe those are the kinds of applications that will be the first uses of these cells, said Dr. Peter Verlander, Chief Scientific Officer for Store-A-Tooth.
When it comes to treating diseases like type 1 diabetes, dental stem cells also show promise. In fact, a study in the Journal of Dental Research found that dental stem cells were able to form islet-like aggregates that produce insulin.
Unlike umbilical cord blood where theres one chance to collect stem cells, dental stem cells can be collected from several teeth. Also, gathering stem cells from bone marrow requires invasive surgery and risk, and it can be painful and costly.
The stem cells found in baby teeth, known as mesenchymal cells, are similar to those found in other parts of the body, but not identical.
There are differences in these cells, depending on where they come from, Verlander said.
Whats more, mesenchymal stem cells themselves differ from hematopoietic, or blood-forming stem cells. Unlike hematopoietic stem cells, mesenchymal stem cells can expand.
From one tooth, we expect to generate hundreds of billions of cells, Verlander said.
Yet the use of dental stem cells is not without risks. For example, theres evidence that tumors can develop when stem cells are transplanted. Theres also a chance of an immune rejection, but this is less likely if a person uses his own stem cells, Miller said.
The process for banking stem cells from baby teeth is relatively simple. A dentist extracts the childs teeth when one-third of the root remains and the stem cells are still viable. Once the teeth are shipped and received, the cells are extracted, grown and cryopreserved.
Store-A-Tooths fees include a one-time payment of $1,749 and $120 per year for storage, in addition to the dentists fees for extraction.
For families who are interested in banking dental stem cells, they should know that theyre not necessarily a replacement for cord blood banking or bone marrow stem cells.
Theyre not interchangeable, we think of them as complementary, Verlander said.
Although the future is unclear for Junowho was born in 2008her mom is optimistic that shell be able to use the stem cells for herself and if not, someone else.
Ultimately, however, Wozniak hopes that if dental stem cells arent the answer, there will be a biological cure for type 1 diabetes.
I hold out hope that somewhere, someone is going to crack the code, she said.
Julie Revelant is a health journalist and a consultant who provides content marketing and copywriting services for the healthcare industry. She’s also a mom of two. Learn more about Julie at revelantwriting.com.
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Can banking baby teeth treat diabetes? – Fox News
Scientists discover an unexpected influence on dividing stem cells …
When it divides, a stem cell has a choice: produce more stem cells or turn into the specific types of cells that compose skin, muscle, brain, or other tissue.
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Scientists discover an unexpected influence on dividing stem cells … – Science Daily
Induced pluripotent stem cells don't increase genetic mutations
Using skin cells from the same donor, they created genetically identical copies of the cells using both the iPSC and the subcloning techniques. They then sequenced the DNA of the skin cells as well as the iPSCs and the subcloned cells and determined …
In 2016, scientists in Japan revealed the birth of mice from eggs made from a parent’s skin cells, and many researchers believe the technique could one day be applied to humans.
The process, called in vitro gametogenesis, allows eggs and sperm to be created in a culture dish in the lab.
Though most scientists agree we’re still a long way off from doing it clinically, it’s a promising technology that has the potential to replace traditional in vitro fertilization to treat infertility.
If and when this process is successful in humans, the implications would be immense, but scientists are now raising legal and ethical questions that need to be addressed before the technology becomes a reality.
In vitro gametogenesis, or IVG, is similar to IVF — in vitro fertilization — in that the joining of egg and sperm takes place in a culture dish.
Trounson believes IVG can provide hope for couples when IVF is not an option.
This procedure can “help men or women who have no gametes — no sperm or eggs,” said Trounson, a renowned stem cell scientist best known for developing human IVF with Carl Wood in 1977.
Another potential benefit with IVG is that there is no need for a woman to receive high doses of fertility drugs to retrieve her eggs, as with traditional IVF.
In addition, same-sex couples would be able to have biological children, and people who lost their gametes through cancer treatments, for instance, would have a chance at having biological children.
In theory, a single woman could also conceive on her own, a concept that Sonia M. Suter, professor of law at George Washington University, calls “solo IVG.” She points out that it comes with some risk, as there will be less genetic variety among the babies.
She added that the risk is even greater than with cloning and although you could use genetic diagnosis to find disease in embryos before implantation, it wouldn’t fully reduce the risk.
This all contributes to the fact that IVG is much more complicated than one might think, and experts add that the process will be even more complex in humans than in mice.
“It’s a much tougher prospect to do this in a human — much, much tougher. It’s like climbing a few stairs versus climbing a mountain,” Trounson said.
“Gametogenesis (in a mouse) is much faster. Everything is much faster and less complicated than you have in a human. So you’ve got to make sure there’s very long intervals to get you the right outcome. … Life, gametogenesis, everything, is much, much briefer than it is in a human.”
Most scientists are reluctant to commit to an exact time frame, but it’s probably safe to say they’re many years away.
Knoepfler used the example of an unapproved and, he says, potentially dangerous three-person baby produced in Mexico in 2016 by a US doctor without FDA approval.
Creating a three-person baby involves a process known as pronuclear transfer, in which an embryo is created using genetic material from three people — the intended mother and father and an egg donor — to remove the risk of genetic diseases caused by DNA in a mother’s mitochondria. The mitochondria are parts of a cell used to create energy but also carry DNA that is passed on only through the maternal line.
This process recently received approval in the UK, but it remains illegal in many countries, including the US.
“Because it seems rogue biomedical endeavors are on the increase, someone could try IVG without sufficient data or governmental approval in the next five to 10 years,” Knoepfler said.
“IVG takes us into uncharted territory, so it’s hard to say legal issues that might come up,” he said, adding that “even other more extreme technologies, such as cloning, of the reproductive kind are not technically prohibited in the US.”
For IVG to be researched further, it will be necessary to perform IVF using the derived gametes and then to study the embryos in ways that would involve their destruction. “At a minimum, federal funding could not be used for such work, but what other laws might come into play is less clear,” Knoepler said.
In several countries, the implantation of a fertilized egg is not allowed if it’s been maintained longer than 14 days.
Dr. Mahendra Rao, scientific adviser with the New York Stem Cell Foundation, explained that in the US, scientists can legally make sperm and oocytes (immature eggs) from other cells and perform IVF. But they would not be able to perform implantation, even in animals.
He said there needs to be clarity that this rule doesn’t apply to “synthetic” embryos scientists are building in culture, where there’s no intention of implanting them.
Daley and his co-authors highlight concerns over “embryo farming” and the consequence of parents choosing an embryo with preferred traits.
“IVG could, depending on its ultimate financial cost, greatly increase the number of embryos from which to select, thus exacerbating concerns about parents selecting for their ‘ideal’ future child,” they write.
With a large number of eggs available through IVG, the process might exacerbate concerns about the devaluation of human life, the authors say.
Also worrying is the potential for someone to get hold of your genetic material — such as sloughed-off skin cells — without your permission. The authors raise questions about the legal ramifications and how they would be handled in court.
“Should the law consider the source of the skin cells to be a legal parent to the child, or should it distinguish an individual’s genetic and legal parentage?” they ask.
As new forms of assisted reproductive technology stretch our ideas about identity, parentage and existing laws and regulations around stem cell research, researchers highlight the need to address these thoughts and have answers in place before making IVG an option.
See the article here:
Could we one day make babies from only skin cells? – CNN
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SOURCE Laboratoire Fleur de Sante
Stem cells are often in the news. These days its usually about some advance in research. Sometimes the controversy about using embryonic stem cells resurfaces. Despite all the coverage (pro or con) stem cells are not well understood. What are they and why are they important?
In more ways than one, its the potential of stem cells that makes them important. At the moment most of the work with stem cells is still in the laboratory; but thats changing. Within the next few years stem cells, in one form or another, will be at work in medical applications such as repairing a damaged pancreas or a heart. In fact, stem cells will be used to repair or even re-grow tissues all over the body skin, liver, lungs, bone marrow. The production of stem cells, their delivery, and procedures for using them will become the basis of an industry. In the not too distant future stem cells, or the knowledge we gain from working with them, will be used in sophisticated repair of the brain and as part of the development of replacement organs. The potential is enormous.
What are stem cells?
Stem cells are found in most multicellular creatures and come in different varieties; all have an important ability: They can fully reproduce themselves almost indefinitely. For example, in mammals like human beings, blood stem cells (hematopoietic stem cells) are active all our lives in the marrow of bones, where they continually produce the many different kinds of blood cells. Therein is another key property for most stem cells; they can become other kinds of cells. The word for this process is differentiate; blood stem cells can differentiate into red blood cells, white blood cells, blood platelets and so forth. The ability to produce different kinds of cells is why stem cells may be used, for example, to repair or replace damaged heart cells something mature heart cells cannot do on their own.
Stem cell jargon
When you read about stem cells, there are a number of words that jump out jargon, yes, but still descriptive. Stem cells are classified by their potency, that is, what other kinds of cells they can become, or put another way, their ability to differentiate into other cells. There is a rank order from more to less potent:
Totipotent sometimes also called omnipotent stem cells can construct a complete and viable organism. In short, they are the same as a cell created by the fusion of the egg and a sperm (an embryonic cell). Totipotent cells can become any type of cell.
Pluripotent stem cells are derived from totipotent cells and are nearly as versatile. They can become any type of cell, except embryonic.
Multipotent stem cells can become a wide variety of cells, but only those of a close family, for example blood stem cells (hematopoietic cells) can become any of the blood cells, but not other kinds of cells.
Oligopotent stem cells are limited to becoming specific types of cells, such as endoderm, ectoderm, and mesoderm.
Unipotent stem cells can only produce cells of their own type, for example skin cells. They can renew themselves (replicate indefinitely), which distinguishes them from non-stem cells.
To a certain extent the potency of a stem cell relates to its usefulness. In one view of an ideal (lab) world, only totipotent stem cells would be used because they can become any other kind of cell. The real world (lab or otherwise) doesnt work that way. For one thing, stem cells of lesser versatility than totipotent cells are valuable for use in specific applications. Even unipotent stem cells, lowest on the potency poll, are arguably better suited for some targeted uses than more generic stem cells. Most importantly, for many uses, especially for medical purposes, pluripotent stem cells are extremely versatile and less controversial.
Avoiding embryonic stem cells
The true totipotent stem cell is a fertilized egg one embryonic cell. To obtain it means detecting and collecting the cell shortly after fertilization and before it begins to divide. Collecting embryonic stem cells one at a time is very difficult and very expensive. Also, in some parts of the world, using embryonic stem cells is highly controversial, usually on religious grounds. Collecting embryonic stem cells can be considered abortion, since the procedure means the cell(s) will not become an embryo. The label abortion is also applied to collecting embryonic stem cells (by gastrulation) shortly after the first fertilized cell begins to divide. These cells, obviously more numerous, are pluripotent and have been the mainstay of stem cell research.
The history of opposition to the use of embryonic stem cells goes back to the 1990s, when stem cell research was in its own infancy. At that time the only source of viable laboratory stem cells was from in vitro living donors. Most of these were harvested from fertilization clinics. They were so difficult to acquire that only a few stem cell lines (painstakingly cultivated generations of embryonic stem cells) were available. Even those were controversial. The United States banned the taking of embryonic stem cells except for 23 grandfathered lines. (This ban was lifted in 2009.)
The controversy over embryonic stem cells can be avoided primarily in two ways. One way is to use adult stem cells. The word adult is a bit misleading since the cells may be derived from fetuses, newborns, and children, which is why theyre sometimes called somatic stem cells. It means that these stem cells come from relatively mature tissue, cells that are already differentiated to a certain degree. Thats why adult stem cells are almost always classified as multipotent, oligopotent, or unipotent. The other way is to transform adult stem cells into pluripotent stem cells. Many approaches to this transformation are being explored in labs all over the world. Some approaches are derived from fetal/newborn substances such as amniotic fluid and placental or umbilical tissue. Other approaches use mature (differentiated) stem cells, such as those from skin, and genetically modify them until they become pluripotent. Such cells are called induced pluripotent stem cells, often abbreviated as iPSC.
At the moment, it is not possible to say which approaches to stem cell production and application will be the most effective. Even some that seem unlikely (stem cells from skin cells?) may turn out to be the most economical and useful. Still, this is where the payoff for stem cell research lies both in terms of scientific knowledge and in profits for medical applications. Consequently the amount of research work in progress is substantial, and often competitive.
Stem Cell Tourism
Because experimental medical techniques and human desperation can add up to big money, there is a developing market for stem cell applications for a variety of medical disorders. Unfortunately, at least for now, with the exception of blood cell transplants and skin cell treatments, most of these applications are either fraudulent or based on shaky experimental results. In general, most stem cell treatments are at best unethical and often illegal; however, their status around the world is a patchwork quilt of laws and regulations (or their absence). It is a near ideal situation for scam artists to lure desperate people into traveling long distances for stem cell treatment that is illegal in their own country. Hence the name: stem cell tourism.
Tracking the Impact of Stem Cell Research
In relative terms, stem cell research is just getting started. Researchers have been at it since the 1950s; but one of the most important discoveries so far induced pluripotent stem cells dates back to only 2006. This means that stem cells are: a. Not yet well understood and b. Their use in medicine is largely experimental and tentative. Heres a useful listing of what the National Institute of Health (U.S. NIH) considers some of the major open questions about adult stem cells:
How many kinds of adult stem cells exist, and in which tissues do they exist? How do adult stem cells evolve during development and how are they maintained in the adult? Are they leftover embryonic stem cells, or do they arise in some other way? Why do stem cells remain in an undifferentiated state when all the cells around them have differentiated? What are the characteristics of their niche that controls their behavior? Do adult stem cells have the capacity to transdifferentiate, and is it possible to control this process to improve its reliability and efficiency? If the beneficial effect of adult stem cell transplantation is a trophic effect, what are the mechanisms? Is donor cell-recipient cell contact required, secretion of factors by the donor cell, or both? What are the factors that control adult stem cell proliferation and differentiation? What are the factors that stimulate stem cells to relocate to sites of injury or damage, and how can this process be enhanced for better healing? [Source: U.S. National Institute of Health]
SciTechStory Impact Area: Stem Cells
Theres not much debate on the importance of stem cell research. It has already had major impact on our understanding of cell biology, and it will provide more. It is just beginning to have an impact on medicine, with much more to come. In fact, news about stem cell research already occurs once or twice a week (on average) that pace is likely to increase. As a matter of keeping up, its necessary to attempt sorting lab work from practical application, which is to say sorting promise from delivery. Even at that it will be difficult to select which stem cell stories are significant.
February 8, 2017 Blood stem cells from patients with Diamond-Blackfan anemia dont mature properly (right two columns). Credit: Doulatov et al., Science Translational Medicine (2017)
Researchers at Boston Children’s Hospital’s Stem Cell Research Program were able, for the first time, to use patients’ own cells to create cells similar to those in bone marrow, and then use them to identify potential treatments for a blood disorder. The work was published today by Science Translational Medicine.
The team derived the so-called blood progenitor cells from two patients with Diamond Blackfan anemia (DBA), a rare, severe blood disorder in which the bone marrow cannot make enough oxygen-carrying red blood cells. The researchers first converted some of the patients’ skin cells into induced pluripotent stem (iPS) cells. They then got the iPS cells to make blood progenitor cells, which they loaded into a high-throughput drug screening system. Testing a library of 1,440 chemicals, the team found several that showed promise in a dish. One compound, SMER28, was able to get live mice and zebrafish to start churning out red blood cells.
The study marks an important advance in the stem cell field. iPS cells, theoretically capable of making virtually any cell type, were first created in the lab in 2006 from skin cells treated with genetic reprogramming factors. Specialized cells generated by iPS cells have been used to look for drugs for a variety of diseasesexcept for blood disorders, because of technical problems in getting iPS cells to make blood cells.
“iPS cells have been hard to instruct when it comes to making blood,” says Sergei Doulatov, PhD, co-first author on the paper with Linda Vo and Elizabeth Macari, PhD. “This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”
DBA currently is treated with steroids, but these drugs help only about half of patients, and some of them eventually stop responding. When steroids fail, patients must receive lifelong blood transfusions and quality of life for many patients is poor. The researchers believe SMER28 or a similar compound might offer another option.
“It is very satisfying as physician scientists to find new potential treatments for rare blood diseases such as Diamond Blackfan anemia,” says Leonard Zon, MD, director of Boston Children’s Stem Cell Research Program and co-corresponding author on the paper with George Q. Daley, MD, PhD. “This work illustrates a wonderful triumph,” says Daley, associate director of the Stem Cell Research Program and also dean of Harvard Medical School.
Making red blood cells
As in DBA itself, the patient-derived blood progenitor cells, studied in a dish, failed to generate the precursors of red blood cells, known as erythroid cells. The same was true when the cells were transplanted into mice. But the chemical screen got several “hits”: in wells loaded with these chemicals, erythroid cells began appearing.
Because of its especially strong effect, SMER28 was put through additional testing. When used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that in turn made red blood cells, reversing or stabilizing anemia. The same was true in cells from DBA patients transplanted into mice. The higher the dose of SMER28, the more red blood cells were produced, and no ill effects were found. (Formal toxicity studies have not yet been conducted.)
Circumventing a roadblock
Previous researchers have tried for years to isolate blood stem cells from patients. They have sometimes succeeded, but the cells are very rare and cannot create enough copies of themselves to be useful for research. Attempts to get iPS cells to make blood stem cells have also failed.
The Boston Children’s researchers were able to circumvent these problems by instead transforming iPS cells into blood progenitor cells using a combination of five reprogramming factors. Blood progenitor cells share many properties with blood stem cells and are readily multiplied in a dish.
“Drug screens are usually done in duplicate, in tens of thousands of wells, so you need a lot of cells,” says Doulatov, who now heads a lab at the University of Washington. “Although blood progenitor cells aren’t bona fide stem cells, they are multipotent and they made red cells just fine.”
SMER28 has been tested preclinically for some neurodegenerative diseases. It activates a so-called autophagy pathway that recycles damaged cellular components. In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Doulatov plans to further explore how this interferes with red blood cell production.
Explore further: Scientists find that persistent infections in mice exhaust progenitors of all blood cells
More information: “Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors,” Science Translational Medicine stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aah5645
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Human skin can be morphed into genetically modified, cancer-killing brain stem cells, according to a new study. This latest advance has only been tested in mice but eventually, its possible that it could be translated into a personalized treatment for people with a deadly form of brain cancer.
The study builds on an earlier discovery that brain stem cells have a weird affinity for cancers. So researchers, led by Shawn Hingtgen, a professor at University of North Carolina at Chapel Hill, created genetically engineered brain stem cells out of human skin. Then they armed the stem cells with drugs to squirt directly onto the tumors of mice that had been given a human form of brain cancer. The treatment shrank the tumors and extended survival of the mice, according to results recently published in the journal Science Translational Medicine.
The treatment shrank the tumors and extended survival
Usually we think about stem cell therapy in the context of rebuilding or regrowing a broken body part like a spinal cord. But if they could be modified to become cancer-fighting homing missiles, it would give patients with a deadly and incurable brain cancer called glioblastoma a better chance at survival. Glioblastomas typically affect adults, and are highly fatal because they send out a web of cancerous threads. Even when the main mass is removed, those threads remain despite chemotherapy and radiation treatment. This cancer has caused a number of high-profile deaths including Senator Edward (Ted) Kennedy in 2009, and possibly Beau Biden more recently. Approximately 12,000 new cases of glioblastoma are estimated to be diagnosed in 2017.
We really have no drugs, no new treatment options in years to even decades, Hingtgen says. [We] just really want to create new therapy that can stand a chance against this disease.
But theres a problem: brain stem cells arent exactly easy to get. Brain stem cells, more properly known as neural stem cells, hang out in the walls of the brains irrigation canals areas filled with cerebrospinal fluid, called ventricles. They generate the cells of the nervous system, like neurons and glial cells, throughout our lives.
They could be modified to become cancer-fighting homing missiles
A research group at the City of Hope in California conducted a clinical trial to make sure it was safe to treat glioblastoma patients with genetically engineered neural stem cells. But they used a neural stem cell line that theyd obtained from fetal tissue. Since the stem cells werent the patients own, people who were genetically more likely to reject the cells couldnt receive the treatment at all. For the people who could, treatment with the neural stem cells turned out to be relatively safe although at this phase of clinical trials, it hasnt been particularly effective.
More personalized treatments have been held up by the challenge of getting enough stem cells out of the patients own brains, which is virtually impossible, says stem cell scientist Frank Marini at the Wake Forest School of Medicine, who was not involved in this study. You cant really generate a bank of neural stem cells from anybody because you have to go in and resect the brain.
So instead, Hingtgen and his colleagues figured out a way to generate neural stem cells from skin which in the future, could let them make neural stem cells personalized to each patient. For this study, though, Hingtgen and his colleagues extracted the skin cells from chunks of human flesh leftover as surgical waste. That really is the magic piece here, Marini says. Now, all of a sudden we have a neural stem cell that can be used as a tumor-homing vehicle.
That really is the magic piece here.
Using a disarmed virus to infect the cells with a cocktail of new genes, the researchers morphed the skin cells into something in between a skin cell and a neural stem cell. People have turned skin cells back into a more generalized type of stem cell before. But then turning those basic stem cells into stem cells for a certain organ like the brain takes another couple of steps, which takes more time. Thats something that people with glioblastoma dont have.
The breakthrough here is that Hingtgens team figured out how to go straight from skin cells to something resembling a neural stem cell in just four days. The researchers then genetically engineered these induced neural stem cells to arm them with one of two different weapons: One group was equipped with an enzyme that could convert an anti-fungal drug into chemotherapy, right at the cancers location. The other was armed with a protein that binds to the cancer cells and makes them commit suicide in an orderly process called apoptosis.
The researchers tested these engineered neural stem cells in mice that had been injected with human glioblastoma cells, which multiplied out of control to create a human cancer in a mouse body. Both of the weaponized stem cell groups were able to significantly shrink the tumors and keep the mice alive by about an extra 30 days (for scale, mice usually live an average of two years).
Were working as fast as we can.
But injecting the cells directly into the tumor doesnt really reflect how the therapy would be used in humans. Its more likely that a person with glioblastoma would get the bulk of the tumor surgically removed. Then, the idea is that these neural stem cells, generated from the patients own skin, will be inserted into the hole left in the brain. So, the researchers tried this out in mice, and the tumors that regrew after surgery were more than three times smaller in the mice treated with the neural stem cells.
Its a promising start, but it could take a few years still before its in the clinic, Hingtgen says. He and his colleagues started a company called Falcon Therapeutics to drive this new therapy forward. Were working as fast as we can, Hingtgen says. We probably cant help the patients today. Hopefully in a year or two, well be able to help those patients.
One of the things theyll have to figure out first is whether the neural stem cells can travel the much bigger distances in human brains, and whether theyll be able to eliminate every remaining cancer cell. The caveats on this are that, of course, its a mouse study, and whether or not that directly converts to humans is unclear, Marini says. Still, he adds, Theres a very high probability in this case.
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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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.
Read more from the original source:
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.
AIVITA Biomedical to Present Skin Care Technology and Products at 15th Annual South Beach Symposium – PR Newswire (press release)
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.
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. 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.
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. 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. 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.
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”. 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. Straub continued to work on actin, and in 1950 reported that actin contains bound ATP 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.
The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973. The crystal structure of G-actin was solved in 1990 by Kabsch and colleagues. In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins. 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. 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.
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. 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.
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. 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.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.
Actin is one of the most abundant proteins in eukaryotes, where it is found throughout the cytoplasm. 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). 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. 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; and in archaea the homologue Ta0583 is even more similar to the eukaryotic actins.
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.
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). 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.
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.
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.
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.
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.
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.
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. 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. 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.
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.
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”. 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). 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.
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. 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.
Actin can spontaneously acquire a large part of its tertiary structure. 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.
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.
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. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 amino acids long, specifically those at the N-terminal.
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). The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.
The CCT then causes actin’s sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity. 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. 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.
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.
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. 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.
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. 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.
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.
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, 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.
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. 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”.
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.
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. 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. 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. 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, which means that at higher values polymerization occurs and at lower values depolymerization occurs.
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. 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.
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:
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. 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.
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. 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. 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.
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.
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). 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.
The Arp2/3 complex is widely found in all eukaryotic organisms. 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).
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:
The actin protein is found in both the cytoplasm and the cell nucleus. 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. 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.
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. 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:
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.
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.
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. 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.
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.
The most notable proteins associated with the actin cytoskeleton in plants include: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);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. 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.) 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. 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.
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).
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.
Based on the experimental results a general mechanism of nuclear actin transport can be proposed:
Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers. 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.
In somatic cell nucleus however we cannot observe any actin filaments using this technique. 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.
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.
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. 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.
Research concerns on nuclear actin are usually focused on isoform beta. 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.
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.
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). These myofibrils use energy derived from ATP to create movements of cells, such as muscle contraction. 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. Tropomyosins regulatory function depends on its interaction with troponin in the presence of Ca2+ ions.
Both actin and myosin are involved in muscle contraction and relaxation and they make up 90% of muscle protein. 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:
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. 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.
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. Its DNA sequence consists of seven exons that produce five known transcripts. 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.
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). 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. 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.
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. 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. 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. 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.
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. 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.
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. 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. The -actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.
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. It was the first of the six genes where alleles were found that were implicated in pathological processes.
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.
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.
The mutations inACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies. The existence of a number of point mutations have also been found:
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.
Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy, and noncompaction of the left ventricular myocardium.
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). A new form of actin has been discovered, kappa actin, which appears to substitute for -actin in processes relating to tumours.
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. 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.
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.
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. 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.
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.
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.
The role that actin plays in the invasion process of cancer cells has still not been determined.
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%. 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.
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. 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.
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. 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. 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 and excessive water loss. 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.
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.
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. 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.[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.
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 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.
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.
There are at least five different pigments that determine the color of the skin. 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.
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.
The Fitzpatrick scale 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.
Cortisol causes degradation of collagen, accelerating skin aging.
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.
Skin performs the following functions:
The human skin is a rich environment for microbes. 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.”
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.
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.
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. 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. When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples. The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging, 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. Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck.
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. 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. Research confirms that nanoparticles larger than 40nm do not penetrate the skin past the stratum corneum. 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. 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.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.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.
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. 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. The UVRs high energy causes a restructuring of cells, weakening the boundary between the stratum corneum and the epidermal layer. 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. 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.
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.
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.
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.
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.
Sunblock and sunscreen are different important skin-care products though both offer full protection from the sun.
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.
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. 
Several scientific studies confirmed that changes in baseline nutritional status affects skin condition. 
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.
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
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Rejuvenating Skin Serum – Stem Cell Nutrition