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Archive for the ‘Bone Marrow Stem Cells’ Category

Quebec family hopes to raise awareness for patients in need with stem cell registry drive – Globalnews.ca

Its been a long and difficult road for West Island resident Kevin Butterfill and his Fiance Natasha Camacho-Gomes.

Kevin had testicular cancer in Oct. 2015, he did chemo, he then had the tumor removed and he was in remission, Gomes said.

Its what happened in July 2016 that is causing a lot of grief for Butterfills loved ones.

He proposed to Camacho-Gomes, his girlfriend since 2009, but a week later more health complications arose.

He was diagnosed with myelodysplastic syndrome (MDS) which is a bone marrow disorder.

And to make matters even worse, Butterfill found out the MDS transformed into acute myeloid leukemia in January.

The past two years have been a roller coaster ride for Kevins mother, Heather Butterfill.

Were staying strong, Heather Butterfill said. Im very faithful that hes going to come out of this stronger than ever.

On Saturday, family and friendsgathered at a Provigo grocery store in Kirkland, encouraging those who know Kevin to sign-up to the bone marrow registry.

READ MORE:Venclexta gets accelerated approval to treat leukemia

Butterfill will need a bone marrow stem cell transplant to recover from the leukemia.

However, according to Hema-Qubec stem cell registry manager Susie Joron, the odds of the perfect match being a friend are slim.

Theres 60,000 transplants every year worldwide, Joron said. The chances of having a friend or a neighbour being matched to that one person that we know is very unlikely.

Gomes said the aim of the event is raise awareness about the stem cell donor registry.

A lot of people were interested in joining and trying to see if they were Kevins match, Camacho-Gomes said.

But a really important thing [to note] is that when you join the stem cell registry youre tested against everyone, so you have the potential to save anyones life.

Regardless of who ends up being Butterfills perfect match, friends like Jonathan Coleman are still hoping they can help.

To hear something like this happen to somebody like that, a good-hearted kid, it sucks and sad to hear, Coleman said. You want do anything you can to help him out.

READ MORE:Id do it again in a heartbeat: debunking myths around stem cell donation as #MenGiveLife kicks off

While Butterfill awaits news of a bone marrow donor for his stem cell transplant, Gomes will hope for a perfect match and move on to planning their wedding.

They set a tentative date for Victoria Day 2018.

For more information on stem cell donation and the registry, visit the Hma-Quebec website.

2017Global News, a division of Corus Entertainment Inc.

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Quebec family hopes to raise awareness for patients in need with stem cell registry drive - Globalnews.ca

Search goes on for bone marrow match for little Longworth lad … – Oxford Mail

ANDREW and Judy Kim are still searching the globe for a donor for their two-year-old son after he was diagnosed with a rare genetic condition.

The couple's son Alastair was diagnosed with chronic granulomatous disorder (CGD) in February last year.

Mr and Mrs Kim launched an appeal for help in September but the search is still on for a matching donor and their son still needs hospital treatment.

The life-threatening condition wipes out his immune system, meaning even the most minor infections leave him seriously ill.

A course of genetic therapy treatment to help him fight infections has been launched and Alastair has been treated at Oxford Children's Hospital and Great Ormond Street Hospital in London.

The only hope of a permanent cure lies in a bone marrow stem cell donor but it needs to be a 90 per cent genetic match and the family is calling for more East Asians to sign up as donors.

Mr Kim, 37, a medical research engineer, said: "It is not easy to find a match and we pray every day that it will work out.

"We have to make sure that Alastair does not get a cut because it could get infected and he does not have the ability to fight off bacteria.

"That could cascade down the line to something very dangerous for him.

"If we get ill then we have to stay away from him he loves our dog Choco Pie but he is not allowed to stroke her.

"We are doing our best to stay positive and raise awareness about his condition."

Mr and Mrs Kim, who live near Longworth with their other son Micah, five, have already searched the international register of more than four million donors but without success.

They are both of Korean descent so a matching donor will most likely be of Korean, Japanese or Chinese heritage.

The number of East Asians on international donor registers is very limited of the 617,000 registered donors in the UK just 0.5 per cent are east Asian.

The couple, who moved to Oxfordshire from Chicago nine years ago, are now appealing for people around the world, particularly East Asians, to order a free kit through a website they have set up, and take a two-minute home test to see if they could help.

Alastair has had numerous infections since he was born in September 2014.

He spent the first year-and-a-half of his life in and out of hospital but CGD is so rare, doctors never thought to test him for it but eventually a doctor at the John Radcliffe Hospital in Oxford decided to test Alastair for the condition.

The couple desperately want to find a matching donor, but also want to increase the number of East Asians on the donor register.

The couple have run several blood drives at Mrs Kim's office at Oxford University and at Harwell Oxford.

More than 90 people came forward and of those, five were able to donate blood that helped Alastair to fight infections.

Mr Kim added: "At a couple of blood drives we have found matches for other people and hopefully one day a match will found for Alastair."

To join the register go to allysfight.com

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Search goes on for bone marrow match for little Longworth lad ... - Oxford Mail

Yes there’s hope, but treating spinal injuries with stem cells is not a reality yet – The Conversation AU

The 2017 Australian of the Year award went to Professor Alan Mackay-Sim for his significant career in stem cell science.

The prize was linked to barbeque-stopping headlines equating his achievements to the scientific equivalent of the moon landing and paving the road to recovery for people with spinal cord injuries.

Such claims in the media imply that there is now a scientifically proven stem cell treatment for spinal cord injury. This is not the case.

For now, any clinic or headline claiming miracle cures should be viewed with caution, as they are likely to be trading on peoples hope.

Put simply, injury to the spinal cord causes damage to the nerve cells that transmit information between the brain and the rest of the body.

Depending on which part of the spine is involved, the injury can affect the nerves that control the muscles in our legs and arms; those that control bowel and bladder function and how we regulate body temperature and blood pressure; and those that carry the sensation of being touched. This occurs in part because injury and subsequent scarring affect not just the nerves but also the insulation that surrounds and protects them. The insulation the myelin sheath is damaged and the body cannot usually completely replace or regenerate this covering.

Stem cells can self-reproduce and grow into hundreds of different cell types, including nerves and the cells that make myelin. So the blue-sky vision is that stem cells could restore some nerve function by replacing missing or faulty cells, or prevent further damage caused by scarring.

Studies in animals have applied stem cells derived from sources including brain tissue, the lining of the nasal cavity, tooth pulp, and embryos (known as embryonic stem cells).

Dramatic improvements have been shown on some occasions, such as rats and mice regaining bladder control or the ability to walk after injury. While striking, such improvement often represents only a partial recovery. It holds significant promise, but is not direct evidence that such an approach will work in people, particularly those with more complex injuries.

The translation of findings from basic laboratory stem cell research to effective and safe treatments in the clinic involves many steps and challenges. It needs a firm scientific basis from animal studies and then careful evaluation in humans.

Many clinical studies examining stem cells for spinal repair are currently underway. The approaches fit broadly into two categories:

using stem cells as a source of cells to replace those damaged as a result of injury

applying cells to act on the bodys own cells to accelerate repair or prevent further damage.

One study that has attracted significant interest involves the injection of myelin-producing cells made from human embryonic stem cells. Researchers hoped that these cells, once injected into the spinal cord, would mature and form a new coating on the nerve cells, restoring the ability of signals to cross the spinal cord injury site. Preliminary results seem to show that the cells are safe; studies are ongoing.

Other clinical trials use cells from patients own bone marrow or adipose tissue (fat), or from donated cord blood or nerves from fetal tissue. The scientific rationale is based on the possibility that when transplanted into the injured spinal cord, these cells may provide surrounding tissue with protective factors which help to re-establish some of the connections important for the network of nerves that carry information around the body.

The field as it stands combines years of research, and tens of millions of dollars of investment. However, the development of stem cell therapies for spinal cord injury remains a long way from translating laboratory promise into proven and effective bedside treatments.

Each case is unique in people with spinal cord injury: the level of paralysis, and loss of sensation and function relate to the type of injury and its location. Injuries as a result of stab wounds or infection may result in different outcomes from those incurred as a result of trauma from a car accident or serious fall. The previous health of those injured, the care received at the time of injury, and the type of rehabilitation they access can all impact on subsequent health and mobility.

Such variability means caution needs to accompany claims of man walking again particularly when reports relate to a single individual.

In the case that was linked to the Australian of the Year award, the actual 2013 study focused on whether it was safe to take the patients own nerves and other cells from the nose and place these into the damaged region of the spine. While the researchers themselves recommended caution in interpreting the results, accompanying media reports focused on the outcome from just one of the six participants.

While the outcome was significant for the gentleman involved, we simply do not know whether recovery may have occurred for this individual even without stem cells, given the type of injury (stab wounds), the level of injury, the accompanying rehabilitation that he received or a combination of these factors. It cannot be assumed a similar outcome would be the case for all people with spinal injury.

Finding a way to alleviate the suffering of those with spinal cord injury, and many other conditions, drives the work of thousands of researchers and doctors around the globe. But stem cells are not a silver bullet and should not be immune from careful evaluation in clinical trials.

Failure to proceed with caution could actually cause harm. For example, a paraplegic woman who was also treated with nasal stem cells showed no clinical improvement, and developed a large mucus-secreting tumour in her spine. This case highlights the need for further refinement and assessment in properly conducted clinical trials before nasal stem cells can become part of mainstream medicine.

Its also worth noting that for spinal cord injury, trials for recovery of function are not limited to the use of stem cells but include approaches focused on promoting health of surviving nerves (neuroprotection), surgery following injury, nerve transfers, electrical stimulation, external physical supports known as exoskeletons, nanotechnology and brain-machine interfaces.

Ultimately, determining which of these approaches will improve the lives of people with spinal injury can only be done through rigorous, ethical research.

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Yes there's hope, but treating spinal injuries with stem cells is not a reality yet - The Conversation AU

Donating Bone Marrow | Cancer.Net

Bone marrow is a soft, spongy material found in your large bones. It makes more than 200 billion new blood cells every day, including red blood cells, white blood cells, and platelets. But for people with bone marrow disease, including several types of cancer, the process doesnt work properly. Often, a bone marrow transplant is a persons best chance of survival and a possible cure. The good news is that donating bone marrow can be as easy and painless as giving blood.

A bone marrow transplant replaces diseased bone marrow with healthy tissue, usually stem cells found in the blood. Thats why bone marrow transplants are also called stem cell transplants. In an allogeneic transplantation (ALLO transplant), blood stem cells from the bone marrow are transplanted from a donor into the patient. The donor stem cells can come from either the blood that circulates throughout another persons body or from umbilical cord blood.

But theres a catch. Before a person receives an ALLO transplant, a matching donor must be found using human leukocyte antigen (HLA) typing. This special blood test analyzes HLAs, which are specific proteins on the surface of white blood cells and other cells that make each persons tissue type unique. HLA-matched bone marrow is less likely to cause a possible side effect of transplantation called graft vs. host disease (GVHD). GVHD is when immune cells in the transplanted tissue recognize the recipients body as foreign and attack it.

Only about 30% of people who need a transplant can find an HLA-matched donor in their immediate family. For the remaining 70% of people, doctors need to find HLA-matched bone marrow from other donors. In 2016, that equals about 14,000 people from very young children up to older adults in the United States who need to find a donor outside of their close family.

The National Marrow Donor Program (NMDP) has a registry of potential donors that might be the match a patient needs. Heres how the donation process works:

You register with the NMDP online or in person at a donor center. You can find a center by calling the toll-free number 1-800-MARROW2.

You collect cells from your cheek with a cotton swab or provide a small blood sample. This is done by following directions in a mail-in kit or at a donor center. The sample is analyzed to determine your HLA type, which is recorded in the NMDP national database.

If an HLA match is made with a patient in need, the NMDP contacts you. A donor center takes a new sample of your blood, which is sent to the patients transplant center to confirm the HLA match. Once doctors confirm the match, youd meet with a counselor from the NMDP to talk about the procedures, benefits, and risks of the donation process. You then decide whether youre comfortable with donating.

If you agree to donate bone marrow, youll likely do whats called a peripheral blood stem cell (PBSC) collection. Heres how it works:

For 5 days leading up to the donation, youll get a daily 5-minute injection of granulocyte colony-stimulating factor (G-CSF), a white blood cell growth hormone.

On day 5, a trained health care provider will place a needle in each of your arms. One needle will remove blood, and a machine circulates the blood and collects the stem cells. Your blood then is returned to your body through the second needle. The process takes about 3 hours and may be repeated on a second donation day. Side effects include headaches, bone soreness, and discomfort from the needles during the process.

Although less common, some donors may be asked to undergo a bone marrow harvest, during which doctors take bone marrow from the back of a donors hip bone during surgery. Donors usually go home the same day of the surgery and can return to normal activity within 1 week. Common side effects include nausea, headache, and fatigue, most often related to the anesthesia. Bruising or discomfort in the lower back is also common.

The end result? You could help cure someones disease.

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Donating Bone Marrow | Cancer.Net

Bone Marrow Transplantation | Hematology and Oncology

What is a bone marrow transplant?

Bone marrow transplant (BMT) is a special therapy for patients with certain cancers or other diseases. A bone marrow transplant involves taking cells that are normally found in the bone marrow (stem cells), filtering those cells, and giving them back either to the donor (patient) or to another person. The goal of BMT is to transfuse healthy bone marrow cells into a person after their own unhealthy bone marrow has been treated to kill the abnormal cells.

Bone marrow transplant has been used successfully to treat diseases such as leukemias, lymphomas, aplastic anemia, immune deficiency disorders, and some solid tumor cancers since 1968.

What is bone marrow?

Bone marrow is the soft, spongy tissue found inside bones. It is the medium for development and storage of most of the body's blood cells.

The blood cells that produce other blood cells are called stem cells. The most primitive of the stem cells is called the pluripotent stem cell, which is different than other blood cells with regards to the following properties:

It is the stem cells that are needed in bone marrow transplant.

Why is a bone marrow transplant needed?

The goal of a bone marrow transplant is to cure many diseases and types of cancer. When the doses of chemotherapy or radiation needed to cure a cancer are so high that a person's bone marrow stem cells will be permanently damaged or destroyed by the treatment, a bone marrow transplant may be needed. Bone marrow transplants may also be needed if the bone marrow has been destroyed by a disease.

A bone marrow transplant can be used to:

The risks and benefits must be weighed in a thorough discussion with your doctor and specialists in bone marrow transplants prior to procedure.

What are some diseases that may benefit from bone marrow transplant?

The following diseases are the ones that most commonly benefit from bone marrow transplant:

However, patients experience diseases differently, and bone marrow transplant may not be appropriate for everyone who suffers from these diseases.

What are the different types of bone marrow transplants?

There are different types of bone marrow transplants depending on who the donor is. The different types of BMT include the following:

How are a donor and recipient matched?

Matching involves typing human leukocyte antigen (HLA) tissue. The antigens on the surface of these special white blood cells determine the genetic makeup of a person's immune system. There are at least 100 HLA antigens; however, it is believed that there are a few major antigens that determine whether a donor and recipient match. The others are considered "minor" and their effect on a successful transplant is not as well-defined.

Medical research is still investigating the role all antigens play in the process of a bone marrow transplant. The more antigens that match, the better the engraftment of donated marrow. Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells.

Most of the genes that "code" for the human immune system are on one chromosome. Since we only have two of each chromosome, one we received from each of our parents, a full sibling of a patient in need of a transplant has a one in four chance of having gotten the same set of chromosomes and being a "full match" for transplantation.

The bone marrow transplant team

The group of specialists involved in the care of patients going through transplant is often referred to as the transplant team. All individuals work together to provide the best chance for a successful transplant. The team consists of the following:

An extensive evaluation is completed by the bone marrow transplant team. The decision for you to undergo a bone marrow transplant will be based on many factors, including the following:

For a patient receiving the transplant, the following will occur in advance of the procedure:

Preparation for the donor

How are the stem cells collected?

A bone marrow transplant is done by transferring stem cells from one person to another. Stem cells can either be collected from the circulating cells in the blood (the peripheral system) or from the bone marrow.

If the donor is the person himself or herself, it is called an autologous bone marrow transplant. If an autologous transplant is planned, previously collected stem cells, from either peripheral (apheresis) or harvest, are counted, screened, and ready to infuse.

The bone marrow transplant procedure

The preparations for a bone marrow transplant vary depending on the type of transplant, the disease requiring transplant, and your tolerance for certain medications. Consider the following:

The days before transplant are counted as minus days. The day of transplant is considered day zero. Engraftment and recovery following the transplant are counted as plus days. For example, a patient may enter the hospital on day -8 for preparative regimen. The day of transplant is numbered zero. Days +1, +2, etc., will follow. There are specific events, complications, and risks associated with each day before, during, and after transplant. The days are numbered to help the patient and family understand where they are in terms of risks and discharge planning.

During infusion of bone marrow, the patient may experience the following:

After infusion, the patient may:

After leaving the hospital, the recovery process continues for several months or longer, during which time the patient cannot return to work or many previously enjoyed activities. The patient must also make frequent follow-up visits to the hospital or doctor's office.

When does engraftment occur?

Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells. Depending on the type of transplant and the disease being treated, engraftment usually occurs around day +15 or +30. Blood counts will be checked frequently during the days following transplant to evaluate initiation and progress of engraftment. Platelets are generally the last blood cell to recover.

Engraftment can be delayed because of infection, medications, low donated stem cell count, or graft failure. Although the new bone marrow may begin making cells in the first 30 days following transplant, it may take months, even years, for the entire immune system to fully recover.

What complications and side effects may occur following BMT?

Complications may vary, depending on the following:

The following are complications that may occur with a bone marrow transplant. However, each individual may experience symptoms differently. These complications may also occur alone, or in combination:

Long-term outlook for a bone marrow transplantation

Prognosis greatly depends on the following:

As with any procedure, in bone marrow transplant the prognosis and long-term survival can vary greatly from person to person. The number of transplants being done for an increasing number of diseases, as well as ongoing medical developments, have greatly improved the outcome for bone marrow transplant in children and adults. Continuous follow-up care is essential for the patient following a bone marrow transplant. New methods to improve treatment and to decrease complications and side effects of a bone marrow transplant are continually being discovered.

More here:
Bone Marrow Transplantation | Hematology and Oncology

Bone – Wikipedia

A bone is a rigid organ that constitutes part of the vertebral skeleton. Bones support and protect the various organs of the body, produce red and white blood cells, store minerals and also enable mobility as well as support for the body. Bone tissue is a type of dense connective tissue. Bones come in a variety of shapes and sizes and have a complex internal and external structure. They are lightweight yet strong and hard, and serve multiple functions. Mineralized osseous tissue, or bone tissue, is of two types, cortical and cancellous, and gives a bone rigidity and a coral-like three-dimensional internal structure. Other types of tissue found in bones include marrow, endosteum, periosteum, nerves, blood vessels and cartilage.

Bone is an active tissue composed of different types of bone cells. Osteoblasts and osteocytes are involved in the creation and mineralisation of bone; osteoclasts are involved in the reabsorption of bone tissue. The mineralised matrix of bone tissue has an organic component of mainly collagen called ossein and an inorganic component of bone mineral made up of various salts.

In the human body at birth, there are over 270 bones,[1] but many of these fuse together during development, leaving a total of 206 separate bones in the adult,[2] not counting numerous small sesamoid bones. The largest bone in the body is the thigh-bone (femur) and the smallest is the stapes in the middle ear.

Bone is not a uniformly solid material, but is mostly a matrix. The primary tissue of bone, bone tissue (osseous tissue), is relatively hard and lightweight. Its matrix is mostly made up of a composite material incorporating the inorganic mineral calcium phosphate in the chemical arrangement termed calcium hydroxylapatite (this is the bone mineral that gives bones their rigidity) and collagen, an elastic protein which improves fracture resistance.[3] Bone is formed by the hardening of this matrix around entrapped cells. When these cells become entrapped from osteoblasts they become osteocytes.[citation needed]

The hard outer layer of bones is composed of cortical bone also called compact bone. Cortical referring to the outer (cortex) layer. The hard outer layer gives bone its smooth, white, and solid appearance, and accounts for 80% of the total bone mass of an adult human skeleton.[citation needed] However, that proportion may be much lower, especially in marine mammals and marine turtles, or in various Mesozoic marine reptiles, such as ichthyosaurs,[4] among others.[5]

Cortical bone consists of multiple microscopic columns, each called an osteon. Each column is multiple layers of osteoblasts and osteocytes around a central canal called the Haversian canal. Volkmann's canals at right angles connect the osteons together. The columns are metabolically active, and as bone is reabsorbed and created the nature and location of the cells within the osteon will change. Cortical bone is covered by a periosteum on its outer surface, and an endosteum on its inner surface. The endosteum is the boundary between the cortical bone and the cancellous bone.

Filling the interior of the bone is the cancellous bone also known as trabecular or spongy bone tissue. It is an open cell porous network. Thin formations of osteoblasts covered in endosteum create an irregular network of spaces. Within these spaces are bone marrow and hematopoietic stem cells that give rise to platelets, red blood cells and white blood cells. Trabecular marrow is composed of a network of rod- and plate-like elements that make the overall organ lighter and allow room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass but has nearly ten times the surface area of compact bone.[8]

Bone marrow, also known as myeloid tissue, can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow, but as the child ages it is mostly replaced by yellow, or fatty marrow. In adults, red marrow is mostly found in the bone marrow of the femur, the ribs, the vertebrae and pelvic bones.[citation needed]

Bone is a metabolically active tissue composed of several types of cells. These cells include osteoblasts, which are involved in the creation and mineralization of bone tissue, osteocytes, and osteoclasts, which are involved in the reabsorption of bone tissue. Osteoblasts and osteocytes are derived from osteoprogenitor cells, but osteoclasts are derived from the same cells that differentiate to form macrophages and monocytes. Within the marrow of the bone there are also hematopoietic stem cells. These cells give rise to other cells, including white blood cells, red blood cells, and platelets.

Bones consist of living cells embedded in a mineralized organic matrix. This matrix consists of organic components, mainly collagen "organic" referring to materials produced as a result of the human body and inorganic components, primarily hydroxyapatite and other salts of calcium and phosphate. Above 30% of the acellular part of bone consists of the organic components, and 70% of salts. The strands of collagen give bone its tensile strength, and the interspersed crystals of hydroxyapatite give bone its compressional strength. These effects are synergistic.

The inorganic composition of bone (bone mineral) is primarily formed from salts of calcium and phosphate, the major salt being hydroxyapatite (Ca10(PO4)6(OH)2). The exact composition of the matrix may change over time and with nutrition, with the ratio of calcium to phosphate varying between 1.3 and 2.0 (per weight), and trace minerals such as magnesium, sodium, potassium and carbonate also being found.

The organic part of matrix is mainly composed of Type I collagen. Collagen composes 9095% of the organic matrix, with remainder of the matrix being a homogenous liquid called ground substance consisting of proteoglycans such as hyaluronic acid and chondroitin sulfate. Collagen consists of strands of repeating units, which give bone tensile strength, and are arranged in an overlapping fashion that prevents shear stress. The function of ground substance is not fully known. Two types of bone can be identified microscopically according to the arrangement of collagen:

Woven bone is produced when osteoblasts produce osteoid rapidly, which occurs initially in all fetal bones, but is later replaced by more resilient lamellar bone. In adults woven bone is created after fractures or in Paget's disease. Woven bone is weaker, with a smaller number of randomly oriented collagen fibers, but forms quickly; it is for this appearance of the fibrous matrix that the bone is termed woven. It is soon replaced by lamellar bone, which is highly organized in concentric sheets with a much lower proportion of osteocytes to surrounding tissue. Lamellar bone, which makes its first appearance in humans in the fetus during the third trimester,[16] is stronger and filled with many collagen fibers parallel to other fibers in the same layer (these parallel columns are called osteons). In cross-section, the fibers run in opposite directions in alternating layers, much like in plywood, assisting in the bone's ability to resist torsion forces. After a fracture, woven bone forms initially and is gradually replaced by lamellar bone during a process known as "bony substitution." Compared to woven bone, lamellar bone formation takes place more slowly. The orderly deposition of collagen fibers restricts the formation of osteoid to about 1 to 2m per day. Lamellar bone also requires a relatively flat surface to lay the collagen fibers in parallel or concentric layers.[citation needed]

The extracellular matrix of bone is laid down by osteoblasts, which secrete both collagen and ground substance. These synthesise collagen within the cell, and then secrete collagen fibrils. The collagen fibres rapidly polymerise to form collagen strands. At this stage they are not yet mineralised, and are called "osteoid". Around the strands calcium and phosphate precipitate on the surface of these strands, within a days to weeks becoming crystals of hydroxyapatite.

In order to mineralise the bone, the osteoblasts secrete vesicles containing alkaline phosphatase. This cleaves the phosphate groups and acts as the foci for calcium and phosphate deposition. The vesicles then rupture and act as a centre for crystals to grow on. More particularly, bone mineral is formed from globular and plate structures.[17][18]

There are five types of bones in the human body: long, short, flat, irregular, and sesamoid.[19]

In the study of anatomy, anatomists use a number of anatomical terms to describe the appearance, shape and function of bones. Other anatomical terms are also used to describe the location of bones. Like other anatomical terms, many of these derive from Latin and Greek. Some anatomists still use Latin to refer to bones. The term "osseous", and the prefix "osteo-", referring to things related to bone, are still used commonly today.

Some examples of terms used to describe bones include the term "foramen" to describe a hole through which something passes, and a "canal" or "meatus" to describe a tunnel-like structure. A protrusion from a bone can be called a number of terms, including a "condyle", "crest", "spine", "eminence", "tubercle" or "tuberosity", depending on the protrusion's shape and location. In general, long bones are said to have a "head", "neck", and "body".

When two bones join together, they are said to "articulate". If the two bones have a fibrous connection and are relatively immobile, then the joint is called a "suture".

The formation of bone is called ossification. During the fetal stage of development this occurs by two processes, Intramembranous ossification and endochondral ossification.[citation needed] Intramembranous ossification involves the creation of bone from connective tissue, whereas in the process of endochondral ossification bone is created from cartilage.

Intramembranous ossification mainly occurs during formation of the flat bones of the skull but also the mandible, maxilla, and clavicles; the bone is formed from connective tissue such as mesenchyme tissue rather than from cartilage. The steps in intramembranous ossification are:[citation needed]

Endochondral ossification, on the other hand, occurs in long bones and most of the rest of the bones in the body; it involves an initial hyaline cartilage that continues to grow. The steps in endochondral ossification are:[citation needed]

Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly appear during fetal development, though a few short bones begin their primary ossification after birth. They are responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones. Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by bone, fusing the diaphysis and both epiphyses together (epiphyseal closure).[citation needed] In the upper limbs, only the diaphyses of the long bones and scapula are ossified. The epiphyses, carpal bones, coracoid process, medial border of the scapula, and acromion are still cartilaginous.[21]

The following steps are followed in the conversion of cartilage to bone:

Bones have a variety of functions:

Bones serve a variety of mechanical functions. Together the bones in the body form the skeleton. They provide a frame to keep the body supported, and an attachment point for skeletal muscles, tendons, ligaments and joints, which function together to generate and transfer forces so that individual body parts or the whole body can be manipulated in three-dimensional space (the interaction between bone and muscle is studied in biomechanics).

Bones protect internal organs, such as the skull protecting the brain or the ribs protecting the heart and lungs. Because of the way that bone is formed, bone has a high compressive strength of about 170 MPa (1800 kgf/cm),[3] poor tensile strength of 104121 MPa, and a very low shear stress strength (51.6 MPa).[23][24] This means that bone resists pushing(compressional) stress well, resist pulling(tensional) stress less well, but only poorly resists shear stress (such as due to torsional loads). While bone is essentially brittle, bone does have a significant degree of elasticity, contributed chiefly by collagen. The macroscopic yield strength of cancellous bone has been investigated using high resolution computer models.[25]

Mechanically, bones also have a special role in hearing. The ossicles are three small bones in the middle ear which are involved in sound transduction.

Cancellous bones contain bone marrow. Bone marrow produces blood cells in a process called hematopoiesis.[26] Blood cells that are created in bone marrow include red blood cells, platelets and white blood cells. Progenitor cells such as the hematopoietic stem cell divide in a process called mitosis to produce precursor cells. These include precursors which eventually give rise to white blood cells, and erythroblasts which give rise to red blood cells. Unlike red and white blood cells, created by mitosis, platelets are shed from very large cells called megakaryocytes. This process of progressive differentiation occurs within the bone marrow. After the cells are matured, they enter the circulation. Every day, over 2.5 billion red blood cells and platelets, and 50100 billion granulocytes are produced in this way.

As well as creating cells, bone marrow is also one of the major sites where defective or aged red blood cells are destroyed.

Bone is constantly being created and replaced in a process known as remodeling. This ongoing turnover of bone is a process of resorption followed by replacement of bone with little change in shape. This is accomplished through osteoblasts and osteoclasts. Cells are stimulated by a variety of signals, and together referred to as a remodeling unit. Approximately 10% of the skeletal mass of an adult is remodelled each year.[32] The purpose of remodeling is to regulate calcium homeostasis, repair microdamaged bones from everyday stress, and also to shape and sculpt the skeleton during growth.[citation needed]. Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.[33]

The action of osteoblasts and osteoclasts are controlled by a number of chemical enzymes that either promote or inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in shape. The cells also use paracrine signalling to control the activity of each other.[citation needed] For example, the rate at which osteoclasts resorb bone is inhibited by calcitonin and osteoprotegerin. Calcitonin is produced by parafollicular cells in the thyroid gland, and can bind to receptors on osteoclasts to directly inhibit osteoclast activity. Osteoprotegerin is secreted by osteoblasts and is able to bind RANK-L, inhibiting osteoclast stimulation.[34]

Osteoblasts can also be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue.[citation needed] Increased secretion of osteoid is stimulated by the secretion of growth hormone by the pituitary, thyroid hormone and the sex hormones (estrogens and androgens). These hormones also promote increased secretion of osteoprotegerin.[34] Osteoblasts can also be induced to secrete a number of cytokines that promote reabsorbtion of bone by stimulating osteoclast activity and differentiation from progenitor cells. Vitamin D, parathyroid hormone and stimulation from osteocytes induce osteoblasts to increase secretion of RANK-ligand and interleukin 6, which cytokines then stimulate increased reabsorption of bone by osteoclasts. These same compounds also increase secretion of macrophage colony-stimulating factor by osteoblasts, which promotes the differentiation of progenitor cells into osteoclasts, and decrease secretion of osteoprotegerin.[citation needed]

Bone volume is determined by the rates of bone formation and bone resorption. Recent research has suggested that certain growth factors may work to locally alter bone formation by increasing osteoblast activity. Numerous bone-derived growth factors have been isolated and classified via bone cultures. These factors include insulin-like growth factors I and II, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and bone morphogenetic proteins.[35] Evidence suggests that bone cells produce growth factors for extracellular storage in the bone matrix. The release of these growth factors from the bone matrix could cause the proliferation of osteoblast precursors. Essentially, bone growth factors may act as potential determinants of local bone formation.[35] Research has suggested that trabecular bone volume in postemenopausal osteoporosis may be determined by the relationship between the total bone forming surface and the percent of surface resorption.[36]

A number of diseases can affect bone, including arthritis, fractures, infections, osteoporosis and tumours. Conditions relating to bone can be managed by a variety of doctors, including rheumatologists for joints, and orthopedic surgeons, who may conduct surgery to fix broken bones. Other doctors, such as rehabilitation specialists may be involved in recovery, radiologists in interpreting the findings on imaging, and pathologists in investigating the cause of the disease, and family doctors may play a role in preventing complications of bone disease such as osteoporosis.

When a doctor sees a patient, a history and exam will be taken. Bones are then often imaged, called radiography. This might include ultrasound X-ray, CT scan, MRI scan and other imaging such as a Bone scan, which may be used to investigate cancer. Other tests such as a blood test for autoimmune markers may be taken, or a synovial fluid aspirate may be taken.

In normal bone, fractures occur when there is significant force applied, or repetitive trauma over a long time. Fractures can also occur when a bone is weakened, such as with osteoporosis, or when there is a structural problem, such as when the bone remodels excessively (such as Paget's disease) or is the site of the growth of cancer. Common fractures include wrist fractures and hip fractures, associated with osteoporosis, vertebral fractures associated with high-energy trauma and cancer, and fractures of long-bones. Not all fractures are painful. When serious, depending on the fractures type and location, complications may include flail chest, compartment syndromes or fat embolism. Compound fractures involve the bone's penetration through the skin.

Fractures and their underlying causes can be investigated by X-rays, CT scans and MRIs. Fractures are described by their location and shape, and several classification systems exist, depending on the location of the fracture. A common long bone fracture in children is a SalterHarris fracture.[39] When fractures are managed, pain relief is often given, and the fractured area is often immobilised. This is to promote bone healing. In addition, surgical measures such as internal fixation may be used. Because of the immobilisation, people with fractures are often advised to undergo rehabilitation.

There are several types of tumour that can affect bone; examples of benign bone tumours include osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone, aneurysmal bone cyst, and fibrous dysplasia of bone.

Cancer can arise in bone tissue, and bones are also a common site for other cancers to spread (metastasise) to. Cancers that arise in bone are called "primary" cancers, although such cancers are rare. Metastases within bone are "secondary" cancers, with the most common being breast cancer, lung cancer, prostate cancer, thyroid cancer, and kidney cancer. Secondary cancers that affect bone can either destroy bone (called a "lytic" cancer) or create bone (a "sclerotic" cancer). Cancers of the bone marrow inside the bone can also affect bone tissue, examples including leukemia and multiple myeloma. Bone may also be affected by cancers in other parts of the body. Cancers in other parts of the body may release parathyroid hormone or parathyroid hormone-related peptide. This increases bone reabsorption, and can lead to bone fractures.

Bone tissue that is destroyed or altered as a result of cancers is distorted, weakened, and more prone to fracture. This may lead to compression of the spinal cord, destruction of the marrow resulting in bruising, bleeding and immunosuppression, and is one cause of bone pain. If the cancer is metastatic, then there might be other symptoms depending on the site of the original cancer. Some bone cancers can also be felt.

Cancers of the bone are managed according to their type, their stage, prognosis, and what symptoms they cause. Many primary cancers of bone are treated with radiotherapy. Cancers of bone marrow may be treated with chemotherapy, and other forms of targeted therapy such as immunotherapy may be used.Palliative care, which focuses on maximising a person's quality of life, may play a role in management, particularly if the likelihood of survival within five years is poor.

Osteoporosis is a disease of bone where there is reduced bone mineral density, increasing the likelihood of fractures. Osteoporosis is defined by the World Health Organization in women as a bone mineral density 2.5 standard deviations below peak bone mass, relative to the age and sex-matched average, as measured by Dual energy X-ray absorptiometry, with the term "established osteoporosis" including the presence of a fragility fracture.[43] Osteoporosis is most common in women after menopause, when it is called "postmenopausal osteoporosis", but may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic diseases or as a result of smoking and medications, specifically glucocorticoids. Osteoporosis usually has no symptoms until a fracture occurs. For this reason, DEXA scans are often done in people with one or more risk factors, who have developed osteoporosis and be at risk of fracture.

Osteoporosis treatment includes advice to stop smoking, decrease alcohol consumption, exercise regularly, and have a healthy diet. Calcium supplements may also be advised, as may Vitamin D. When medication is used, it may include bisphosphonates, Strontium ranelate, and osteoporosis may be one factor considered when commencing Hormone replacement therapy.[44]

The study of bones and teeth is referred to as osteology. It is frequently used in anthropology, archeology and forensic science for a variety of tasks. This can include determining the nutritional, health, age or injury status of the individual the bones were taken from. Preparing fleshed bones for these types of studies can involve the process of maceration.

Typically anthropologists and archeologists study bone tools made by Homo sapiens and Homo neanderthalensis. Bones can serve a number of uses such as projectile points or artistic pigments, and can also be made from external bones such as antlers.

Bird skeletons are very lightweight. Their bones are smaller and thinner, to aid flight. Among mammals, bats come closest to birds in terms of bone density, suggesting that small dense bones are a flight adaptation. Many bird bones have little marrow due to their being hollow.[45]

A bird's beak is primarily made of bone as projections of the mandibles which are covered in keratin.

A deer's antlers are composed of bone which is an unusual example of bone being outside the skin of the animal once the velvet is shed.[46]

The extinct predatory fish Dunkleosteus had sharp edges of hard exposed bone along its jaws.[citation needed]

Many animals possess an exoskeleton that is not made of bone, These include insects and crustaceans.

Bones from slaughtered animals have a number of uses. In prehistoric times, they have been used for making bone tools. They have further been used in bone carving, already important in prehistoric art, and also in modern time as crafting materials for buttons, beads, handles, bobbins, calculation aids, head nuts, dice, poker chips, pick-up sticks, ornaments, etc. A special genre is scrimshaw.

Bone glue can be made by prolonged boiling of ground or cracked bones, followed by filtering and evaporation to thicken the resulting fluid. Historically once important, bone glue and other animal glues today have only a few specialized uses, such as in antiques restoration. Essentially the same process, with further refinement, thickening and drying, is used to make gelatin.

Broth is made by simmering several ingredients for a long time, traditionally including bones.

Ground bones are used as an organic phosphorus-nitrogen fertilizer and as additive in animal feed. Bones, in particular after calcination to bone ash, are used as source of calcium phosphate for the production of bone china and previously also phosphorus chemicals.[citation needed]

Bone char, a porous, black, granular material primarily used for filtration and also as a black pigment, is produced by charring mammal bones.

Oracle bone script was a writing system used in Ancient china based on inscriptions in bones.

To point the bone at someone is considered bad luck in some cultures, such as Australian aborigines, such as by the Kurdaitcha.

Osteopathic medicine is a school of medical thought originally developed based on the idea of the link between the musculoskeletal system and overall health, but now very similar to mainstream medicine. As of 2012[update], over 77,000 physicians in the United States are trained in Osteopathic medicine colleges.[47]

The wishbones of fowl have been used for divination, and are still customarily used in a tradition to determine which one of two people pulling on either prong of the bone may make a wish.

Various cultures throughout history have adopted the custom of shaping an infant's head by the practice of artificial cranial deformation. A widely practised custom in China was that of foot binding to limit the normal growth of the foot.

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Stem cells from fat outperform those from bone marrow in …

Durham, NC A new study appearing in the current issue of STEM CELLS Translational Medicine indicates that stem cells harvested from fat (adipose) are more potent than those collected from bone marrow in helping to modulate the bodys immune system.

The finding could have significant implications in developing new stem-cell-based therapies, as adipose tissue-derived stem cells (AT-SCs) are far more plentiful in the body than those found in bone marrow and can be collected from waste material from liposuction procedures. Stem cells are considered potential therapies for a range of conditions, from enhancing skin graft survival to treating inflammatory bowel disease.

Researchers at the Leiden University Medical Centers Department of Immunohematology and Blood Transfusion in Leiden, The Netherlands, led by Helene Roelofs, Ph.D., conducted the study. They were seeking an alternative to bone marrow for stem cell therapies because of the low number of stem cells available in marrow and also because harvesting them involves an invasive procedure.

Adipose tissue is an interesting alternative since it contains approximately a 500-fold higher frequency of stem cells and tissue collection is simple, Dr. Roelofs said.

Moreover, Dr. Sara M. Melief added, 400,000 liposuctions a year are performed in the U.S. alone, where the aspirated adipose tissue is regarded as waste and could be collected without any additional burden or risk for the donor.

For the study, the team used stem cells collected from the bone marrow and fat tissue of age-matched donors. They compared the cells ability to regulate the immune system in vitro and found that the two performed similarly, although it took a smaller dose for the AT-SCs to achieve the same effect on the immune cells.

When it came to secreting cytokines the cell signaling molecules that regulate the immune system the AT-SCs also outperformed the bone marrow-derived cells.

This all adds up to make AT-SC a good alternative to bone marrow stem cells for developing new therapies, Dr. Roelofs concluded.

Cells from bone marrow and from fat were equivalent in terms of their potential to differentiate into multiple cell types, said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of Wake Forest Institute for Regenerative Medicine. The fact that the cells from fat tissue seem to be more potent at suppressing the immune system suggest their promise in clinical therapies.

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Stem cells from fat outperform those from bone marrow in ...

Stem-cell therapy – Wikipedia

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

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

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[70][71][72][73] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[74] Companion animals can serve as clinically relevant models that closely mimic human disease.[75][76]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

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Stem-cell therapy - Wikipedia

Stem cell – Wikipedia

Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cellsectoderm, endoderm and mesoderm (see induced pluripotent stem cells)but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

There are three known accessible sources of autologous adult stem cells in humans:

Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures.

Adult stem cells are frequently used in various medical therapies (e.g., bone marrow transplantation). Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic cell lines and autologous embryonic stem cells generated through somatic cell nuclear transfer or dedifferentiation have also been proposed as promising candidates for future therapies.[1] Research into stem cells grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s.[2][3]

The classical definition of a stem cell requires that it possess two properties:

Two mechanisms exist to ensure that a stem cell population is maintained:

Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.[4]

In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or hematopoietic stem cells (HSCs) is the ability to transplant the cells and save an individual without HSCs. This demonstrates that the cells can produce new blood cells over a long term. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.

Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, in which single cells are assessed for their ability to differentiate and self-renew.[7][8] Stem cells can also be isolated by their possession of a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells shall behave in a similar manner in vivo. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.[citation needed]

Embryonic stem (ES) cells are the cells of the inner cell mass of a blastocyst, an early-stage embryo.[9] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.

During embryonic development these inner cell mass cells continuously divide and become more specialized. For example, a portion of the ectoderm in the dorsal part of the embryo specializes as 'neurectoderm', which will become the future central nervous system.[10] Later in development, neurulation causes the neurectoderm to form the neural tube. At the neural tube stage, the anterior portion undergoes encephalization to generate or 'pattern' the basic form of the brain. At this stage of development, the principal cell type of the CNS is considered a neural stem cell. These neural stem cells are pluripotent, as they can generate a large diversity of many different neuron types, each with unique gene expression, morphological, and functional characteristics. The process of generating neurons from stem cells is called neurogenesis. One prominent example of a neural stem cell is the radial glial cell, so named because it has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall, and because historically it shared some glial characteristics, most notably the expression of glial fibrillary acidic protein (GFAP).[11][12] The radial glial cell is the primary neural stem cell of the developing vertebrate CNS, and its cell body resides in the ventricular zone, adjacent to the developing ventricular system. Neural stem cells are committed to the neuronal lineages (neurons, astrocytes, and oligodendrocytes), and thus their potency is restricted.[10]

Nearly all research to date has made use of mouse embryonic stem cells (mES) or human embryonic stem cells (hES) derived from the early inner cell mass. Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin as an extracellular matrix (for support) and require the presence of leukemia inhibitory factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic fibroblast growth factor (bFGF or FGF-2).[13] Without optimal culture conditions or genetic manipulation,[14] embryonic stem cells will rapidly differentiate.

A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[15] The cell surface antigens most commonly used to identify hES cells are the glycolipids stage specific embryonic antigen 3 and 4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. By using human embryonic stem cells to produce specialized cells like nerve cells or heart cells in the lab, scientists can gain access to adult human cells without taking tissue from patients. They can then study these specialized adult cells in detail to try and catch complications of diseases, or to study cells reactions to potentially new drugs. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[16]

There are currently no approved treatments using embryonic stem cells. The first human trial was approved by the US Food and Drug Administration in January 2009.[17] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal cord injury research. On November 14, 2011 the company conducting the trial (Geron Corporation) announced that it will discontinue further development of its stem cell programs.[18] ES cells, being pluripotent cells, require specific signals for correct differentiationif injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[19] Due to ethical considerations, many nations currently have moratoria or limitations on either human ES cell research or the production of new human ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.

Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer

The primitive stem cells located in the organs of fetuses are referred to as fetal stem cells.[20] There are two types of fetal stem cells:

Adult stem cells, also called somatic (from Greek , "of the body") stem cells, are stem cells which maintain and repair the tissue in which they are found.[22] They can be found in children, as well as adults.[23]

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.[24] Bone marrow is a rich source of adult stem cells,[25] which have been used in treating several conditions including liver cirrhosis,[26] chronic limb ischemia [27] and endstage heart failure.[28] The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.[29] Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.[30] DNA damage accumulates with age in both stem cells and the cells that comprise the stem cell environment. This accumulation is considered to be responsible, at least in part, for increasing stem cell dysfunction with aging (see DNA damage theory of aging).[31]

Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, dental pulp stem cell, etc.).[32][33]

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[34] Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[35]

The use of adult stem cells in research and therapy is not as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, in instances where adult stem cells are obtained from the intended recipient (an autograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.[36]

Multipotent stem cells are also found in amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic. Amniotic stem cells are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.[37] Amniotic stem cells are a topic of active research.

Use of stem cells from amniotic fluid overcomes the ethical objections to using human embryos as a source of cells. Roman Catholic teaching forbids the use of embryonic stem cells in experimentation; accordingly, the Vatican newspaper "Osservatore Romano" called amniotic stem cells "the future of medicine".[38]

It is possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bank [39][40] was opened in 2009 in Medford, MA, by Biocell Center Corporation[41][42][43] and collaborates with various hospitals and universities all over the world.[44]

These are not adult stem cells, but rather adult cells (e.g. epithelial cells) reprogrammed to give rise to pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[45][46][47]Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4[45] in their experiments on human facial skin cells. Junying Yu, James Thomson, and their colleagues at the University of WisconsinMadison used a different set of factors, Oct4, Sox2, Nanog and Lin28,[45] and carried out their experiments using cells from human foreskin.

As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon somatic cell nuclear transfer as an avenue of research.[48]

Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.[49]

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.[50]

An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals decapentaplegic and adherens junctions that prevent germarium stem cells from differentiating.[51][52]

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplant is a form of stem cell therapy that has been used for many years without controversy. No stem cell therapies other than bone marrow transplant are widely used.[53][54]

Stem cell treatments may require immunosuppression because of a requirement for radiation before the transplant to remove the person's previous cells, or because the patient's immune system may target the stem cells. One approach to avoid the second possibility is to use stem cells from the same patient who is being treated.

Pluripotency in certain stem cells could also make it difficult to obtain a specific cell type. It is also difficult to obtain the exact cell type needed, because not all cells in a population differentiate uniformly. Undifferentiated cells can create tissues other than desired types.[55]

Some stem cells form tumors after transplantation;[56] pluripotency is linked to tumor formation especially in embryonic stem cells, fetal proper stem cells, induced pluripotent stem cells. Fetal proper stem cells form tumors despite multipotency.[citation needed]

Some of the fundamental patents covering human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF) they are patents 5,843,780, 6,200,806, and 7,029,913 invented by James A. Thomson. WARF does not enforce these patents against academic scientists, but does enforce them against companies.[57]

In 2006, a request for the US Patent and Trademark Office (USPTO) to re-examine the three patents was filed by the Public Patent Foundation on behalf of its client, the non-profit patent-watchdog group Consumer Watchdog (formerly the Foundation for Taxpayer and Consumer Rights).[57] In the re-examination process, which involves several rounds of discussion between the USTPO and the parties, the USPTO initially agreed with Consumer Watchdog and rejected all the claims in all three patents,[58] however in response, WARF amended the claims of all three patents to make them more narrow, and in 2008 the USPTO found the amended claims in all three patents to be patentable. The decision on one of the patents (7,029,913) was appealable, while the decisions on the other two were not.[59][60] Consumer Watchdog appealed the granting of the '913 patent to the USTPO's Board of Patent Appeals and Interferences (BPAI) which granted the appeal, and in 2010 the BPAI decided that the amended claims of the '913 patent were not patentable.[61] However, WARF was able to re-open prosecution of the case and did so, amending the claims of the '913 patent again to make them more narrow, and in January 2013 the amended claims were allowed.[62]

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US Court of Appeals for the Federal Circuit (CAFC), the federal appeals court that hears patent cases.[63] At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had legal standing to appeal; the case could not proceed until that issue was resolved.[64]

Diseases and conditions where stem cell treatment is being investigated include:

Research is underway to develop various sources for stem cells, and to apply stem cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.[80]

In more recent years, with the ability of scientists to isolate and culture embryonic stem cells, and with scientists' growing ability to create stem cells using somatic cell nuclear transfer and techniques to create induced pluripotent stem cells, controversy has crept in, both related to abortion politics and to human cloning.

Hepatotoxicity and drug-induced liver injury account for a substantial number of failures of new drugs in development and market withdrawal, highlighting the need for screening assays such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.[81]

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Stem cell - Wikipedia

CCR5 – Wikipedia

CCR5 Identifiers Aliases CCR5, CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5, CMKBR5, IDDM22, C-C motif chemokine receptor 5 (gene/pseudogene) External IDs OMIM: 601373 MGI: 107182 HomoloGene: 37325 GeneCards: CCR5 Targeted by Drug aplaviroc, cenicriviroc, maraviroc, vicriviroc[1] Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Chr 3: 46.37 46.38 Mb Chr 9: 124.12 124.15 Mb PubMed search [2] [3] Wikidata View/Edit Human View/Edit Mouse

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Many forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. Certain individuals carry a mutation known as CCR5-32 in the CCR5 gene, protecting them against these strains of HIV.

In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[4][5][6][7][8][9]

The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins.[10][11] It is a G proteincoupled receptor[10] which functions as a chemokine receptor in the CC chemokine group.

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1 and 1, respectively), and CCL3L1.[12][13] CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).[12][14][15]

CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, functional response of the receptor, and HIV co-receptor activity.[16]

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.[17] These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell.[18] The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.[18] The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit, and the Gp41 transmembrane subunit.[18] This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of three Gp120-Gp41 hetero-dimers.[18] The Gp120 envelope protein is a chemokine mimic.[17] It lacks the unique structure of a chemokine, however it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.[17] During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell- forming a heterotrimeric complex.[17] The formation of this complex stimulates the release of a fusogenic peptide inducing the fusion of the viral membrane with the membrane of the target host cell.[17] Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein.[19] Co-receptor recognition also include the V1-V2 region of gp120, and the bridging sheet (an antiparallel, 4-stranded sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity.[19] The normal ligands for this receptor, RANTES, MIP-1, and MIP-1, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[20] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it hasn't been finalized as a proven theory yet, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains [19]

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.[21] Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function.[22] A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with the associative binding between the Gp120 envelope protein and the HIV co-receptor CCR5.[21] These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007.[21] It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor.[19] A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. However, because there is still another co-receptor available, this indicates that lacking the CCR5 gene doesn't make one immune to the virus; it simply implies that it would be more challenging for the individual to contract it. Also, the virus still has access to the CD4. Unlike CCR5, which the body apparently doesn't really need due to those still living healthy lives even with the lack of/or absence of the gene (as a result of the delta 32 mutation), CD4 is critical in the bodies defense system (fighting against infection).[23] Even without the availability of either co-receptors (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail), resulting in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.[24]

CCR5-32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.[25][26]

CCR5 32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor.[27][28] CCR5 is required for M-tropic HIV-1 virus entry.[29] Individuals homozygous for CCR5 32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures.[29] Individuals heterozygous for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface.[30] Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types.[27][29][31] Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment.[32] CCR5 32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.

The CCR5 32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,[33] which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.

Two studies have used linkage analysis to estimate the age of the CCR5 32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 32 deletion would be proportional to the age of the deletion.[26][34] Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), estimated the age of the CCR5 32 mutation is based on the microsatellite mutations to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval).[34] A third hypothesis relies on the on the north-to-south gradient of allele frequency in Europe which shows that the highest allele frequency occurred in Nordic regions such as Iceland, Norway and Sweden and lowest allele frequency in the south. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe was due to the Viking dispersal in the 8th to 10th century.[35] Vikings were later replaced by the Varangians in Russia, which migrated East which may have contributed to the observed east-to-west cline of allele frequency.[33][35]

HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa,[36] through exposure to infected blood and body fluids while butchering bushmeat.[37] However, HIV-1 was effectively absent from Europe until the late 1980s.[38] Therefore, given the average age of roughly 1000 years for the CCR5-32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies.[33] Hence, other pathogens have been suggested agents of positive selection for CCR5 32. The first major one being bubonic plague (Yersinia pestis), and later, smallpox (Variola major). Other data suggest that the allele frequency resulted as a negative selection pressure as a result of pathogens that became more widespread during Roman expansion.[39] The idea that negative selection played a role in its low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.[40][41]

Several lines of evidence suggest that the CCR5 32 allele evolved only once.[33] First, CCR5 32 has a relatively high frequency in several different Caucasian populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,[26] suggesting that a single mutation occurred after divergence of Caucasians from their African ancestor).[26][27][42] Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor.[34] This was demonstrated by showing that the CCR5 32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.[34] This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 32 alleles arose from a single mutational event. Finally, the CCR5 32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).[34]

In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.[26] Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.

It is estimated that HIV-1 entered the human population in Africa in the early 1900s,[36] symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 32 from zero to 10% in 2000 years. In 1998, Stephens et al. suggested that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 32.[26] This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.[43] After the Black Death, there were less severe, intermittent, epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.[43][44][45] In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europes population.[43][46] Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents and spread by fleas and only occasionally infecting humans.[47] Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.[48] Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.[47] Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 32 to 10% in Europe.[25]

To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.[25] Plague was modeled according to historical accounts,[49][50] while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.[44] Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.[25] Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.[51][52] The authors calculated that if plague were selecting for CCR5 32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.

The hypothesis that smallpox exerted positive selection for CCR5 32 is also biologically plausible, since poxviruses, like HIV, are viruses that enter white blood cells by using chemokine receptors.[53] By contrast, Yersinia pestis is a bacterium with a very different biology.

Although Caucasians are the only population with a high frequency of CCR5 32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.[52] By contrast, the CCR5 32 mutation is found only in European, West Asian, and North African populations.[54] The anomalously high frequency of CCR5 32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.

Research has not yet revealed a cost of carrying the CCR5 null mutation that is as dramatic as the benefit conferred in the context of HIV-1 exposure. In general, research suggests that the CCR5 32 mutation protects against diseases caused by certain pathogens but may also play a deleterious role in postinfection inflammatory processes, which can injure tissue and create further pathology.[55] The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus).[56] In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.[57]

This finding in humans confirmed a previously-observed experiment in an animal model of CCR5 32 homozygosity. After infection with West Nile Virus, CCR5 32 mice had markedly increased viral titers in the central nervous system and had increased mortality[58] compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.

CCR5 32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals.[59] When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus resistant cell pool in infected individuals.[59]

This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[5][60] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[5] However, this is consistent with the observation that cells expressing the CCR5-32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[61] After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[6]

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-32 trait and then reintroduced into the body as a potential HIV treatment.[62][63] Results reported in 2014 were promising.[9]

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CCR5 - Wikipedia

JCI – Welcome

BACKGROUND. Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia.

METHODS. We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (1018 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (3238 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin Dassociated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia.

RESULTS. Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.611.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD 30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD

CONCLUSIONS. Vitamin D supplementation initiated in weeks 1018 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin Dassociated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00920621.

FUNDING. Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Hooman Mirzakhani, Augusto A. Litonjua, Thomas F. McElrath, George OConnor, Aviva Lee-Parritz, Ronald Iverson, George Macones, Robert C. Strunk, Leonard B. Bacharier, Robert Zeiger, Bruce W. Hollis, Diane E. Handy, Amitabh Sharma, Nancy Laranjo, Vincent Carey, Weilliang Qiu, Marc Santolini, Shikang Liu, Divya Chhabra, Daniel A. Enquobahrie, Michelle A. Williams, Joseph Loscalzo, Scott T. Weiss

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JCI - Welcome

8 – OMICS International Conference

Conference Series invites all the participants from all over the world to attend"8th European Immunology Conference, June 29-July 01, 2017 Madrid, Spain, includesprompt keynote presentations, Oral talks, Poster presentations and Exhibitions.

European ImmunologyConferenceis to gathering people in academia and society interested inimmunologyto share the latest trends and important issues relevant to our field/subject area.Immunology Conferencesbrings together the global leaders in Immunology and relevant fields to present their research at this exclusive scientific program. TheImmunology Conferencehosting presentations from editors of prominent refereed journals, renowned and active investigators and decision makers in the field of Immunology.European Immunology ConferenceOrganizing Committee also invites Young investigators at every career stage to submit abstracts reporting their latest scientific findings in oral and poster sessions.

Track:1Cellular Immunology

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science ofimmunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired oradaptive immune system

The field concerning the interactions among cells and molecules of the immunesystem,and how such interactions contribute to the recognition and elimination of pathogens. Humans possess a range of non-specific mechanical and biochemical defences against routinely encountered bacteria, parasites, viruses, and fungi. The skin, for example, is an effective physical barrier to infection. Basic chemical defences are also present in blood, saliva, and tears, and on mucous membranes. True protection stems from the host's ability to mount responses targeted to specific organisms, and to retain a form of memory that results in a rapid, efficient response to a given organism upon a repeat encounter. This more formal sense of immunity, termed adaptive immunity, depends upon the coordinated activities of cells and molecules of the immune system.

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Track: 2Inflammatory/Autoimmune Diseases

Autoimmune diseasescan affect almost any part of the body, including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, the digestive tract, and blood vessels.

The classic sign of an autoimmune disease is inflammation, which can cause redness, heat, pain, and swelling. How an autoimmune disease affects you depends on what part of the body is targeted. If the disease affects the joints, as inrheumatoid arthritis, you might have joint pain, stiffness, and loss of function. If it affects the thyroid, as in Graves disease and thyroiditis, it might cause tiredness, weight gain, and muscle aches. If it attacks the skin, as it does in scleroderma/systemic sclerosis, vitiligo, andsystemic lupus erythematosus(SLE), it can cause rashes, blisters, and colour changes. Many autoimmune diseases dont restrict themselves to one part of the body. For example, SLE can affect the skin, joints, kidneys, heart, nerves, blood vessels, and more. Type 1 diabetes can affect your glands, eyes, kidneys, muscles, and more.

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Track: 3T-Cells and B-Cells

T cell: A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders. Immature T cells (termed T-stem cells) migrate to the thymus gland in the neck, where they mature and differentiate into various types of mature T cells and become active in the immune system in response to a hormone called thymosin and other factors. T-cells that are potentially activated against the body's own tissues are normally killed or changed ("down-regulated") during this maturational process.There are several different types of mature T cells. Not all of their functions are known. T cells can produce substances called cytokines such as the interleukins which further stimulate the immune response. T-cell activation is measured as a way to assess the health of patients withHIV/AIDSand less frequently in other disorders. T cell are also known as T lymphocytes. The "T" stands for "thymus" -- the organ in which these cells mature. As opposed to B cells which mature in the bone marrow.B cells, also known asBlymphocytes, are a type of white bloodcellof the lymphocyte subtype. They function in thehumoral immunitycomponent of the adaptive immune system by secreting antibodies. Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells. All of the plasma cells descended from a single B cell produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells "remember" the stimulus that led to their formation. The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow. The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production ofimmunoglobulins.It expresses immunoglobulins on its surface.

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Track: 4Cancer and Tumor Immunobiology

The tumour is an important aspect of cancer biology that contributes to tumour initiation, tumour progression and responses to therapy. Cells and molecules of the immune system are a fundamental component of the tumour microenvironment. Importantly,therapeutic strategies for cancer treatmentcan harness the immune system to specifically target tumour cells and this is particularly appealing owing to the possibility of inducing tumour-specific immunological memory, which might cause long-lasting regression and prevent relapse in cancer patients.The composition and characteristics of the tumour microenvironment vary widely and are important in determining the anti-tumour immune response.Immunotherapyis a new class ofcancer treatmentthat works to harness the innate powers of the immune system to fight cancer. Because of the immune system's unique properties, these therapies may hold greater potential than current treatment approaches to fight cancer more powerfully, to offer longer-term protection against the disease, to come with fewer side effects, and to benefit more patients with more cancer

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Track: 5 Vaccines

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. There are two basictypes of vaccines: live attenuated and inactivated. The characteristics of live and inactivatedvaccinesare different, and these characteristics determine how thevaccineis used. Liveattenuatedvaccinesare produced by modifying a disease-producing (wild) virus or bacteria in a laboratory.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 6Immunotherapy

Immunotherapy,also called biologic therapy, is a type of cancer treatment designed to boost the body's natural defences to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. Immunotherapy is treatment that uses certain parts of a persons immune system to fight diseases such as cancer. This can be done in a couple of ways:1)Stimulating your own immune system to work harder or smarter to attack cancer cells2)Giving you immune system components, such as man-made immune system proteins. Some types of immunotherapy are also sometimes called biologic therapy or biotherapy.

In the last few decadesimmunotherapyhas become an important part of treating some types of cancer. Newer types of immune treatments are now being studied, and theyll impact how we treat cancer in the future. Immunotherapy includes treatments that work in different ways. Some boost the bodys immune system in a very general way. Others help train the immune system to attack cancer cells specifically. Immunotherapy works better for some types of cancer than for others. Its used by itself for some of these cancers, but for others it seems to work better when used with other types of treatment.

Many different types of immunotherapy are used to treat cancer. They include:Monoclonal antibodies,Adoptive cell transfer,Cytokines, Treatment Vaccines, BCG,

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Track: 7Neuro Immunology

Neuroimmunology, a branch of immunologythat deals especially with the inter relationships of the nervous system and immune responses andautoimmune disorders. It deals with particularly fundamental and appliedneurobiology,meetings onneurology,neuropathology, neurochemistry,neurovirology, neuroendocrinology, neuromuscular research,neuropharmacologyand psychology, which involve either immunologic methodology (e.g. immunocytochemistry) or fundamental immunology (e.g. antibody and lymphocyte assays).

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Track: 8Infectious Diseases and Immune System

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi; the diseases can be spread, directly or indirectly, from one person to another.Zoonotic diseasesare infectious diseases of animals that can cause disease when transmitted to humans. Some infectious diseases can be passed from person to person. Some are transmitted by bites from insects or animals. And others are acquired by ingesting contaminated food or water or being exposed to organisms in the environment. Signs and symptoms vary depending on the organism causing the infection, but often include fever and fatigue. Mild complaints may respond to rest and home remedies, while some life-threatening infections may require hospitalization.

Many infectious diseases, such as measles andchickenpox, can be prevented by vaccines. Frequent and thorough hand-washing also helps protect you from infectious diseases

There are four main kinds of germs:

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Track: 9Reproductive Immunology,

Reproductive immunologyrefers to a field of medicine that studies interactions (or the absence of them) between the immune system and components related to thereproductivesystem, such as maternal immune tolerance towards the fetus, orimmunologicalinteractions across the blood-testis barrier. The immune system refers to all parts of the body that work to defend it against harmful enemies. In people with immunological fertility problems their body identifies part of reproductive function as an enemy and sendsNatural Killer (NK) cellsto attack. A healthy immune response would only identify an enemy correctly and attack only foreign invaders such as a virus, parasite, bacteria, ect.

The concept of reproductive immunology is not widely accepted by all physicians.Those patients who have had repeated miscarriages and multiple failed IVF's find themselves exploring it's possibilities as the reason. With an increased amount of success among treating any potential immunological factors, the idea of reproductive immunology can no longer be overlooked.The failure to conceive is often due to immunologic problems that can lead to very early rejection of the embryo, often before the pregnancy can be detected by even the most sensitive tests. Women can often produce perfectly healthy embryos that are lost through repeated "mini miscarriages." This most commonly occurs in women who have conditions such asendometriosis, an under-active thyroid gland or in cases of so called "unexplained infertility." It has been estimated that an immune factor may be involved in up to 20% of couples with otherwiseunexplained infertility. These are all conditions where abnormalities of the womans immune system may play an important role.

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Track:10Auto Immunity,

Autoimmunityis the system ofimmuneresponses of an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases. Autoimmune diseases occur when there is progression from benign autoimmunity to pathogenicautoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Autoimmune disorders

An autoimmune disorder occurs whenthe bodys immune systemattacks and destroys healthy body tissue by mistake. There are more than 80 types of autoimmune disorders.

Causes

The white blood cells in the bodys immune system help protect against harmful substances. Examples include bacteria, viruses,toxins,cancercells, and blood and tissue from outside the body. These substances contain antigens. The immune system producesantibodiesagainst these antigens that enable it to destroy these harmful substances. When you have an autoimmune disorder, your immune system does not distinguish between healthy tissue and antigens. As a result, the body sets off a reaction that destroys normal tissues. The exact cause of autoimmune disorders is unknown. One theory is that some microorganisms (such as bacteria or viruses) or drugs may trigger changes that confuse the immune system. This may happen more often in people who have genes that make them more prone toautoimmune disorders.

An autoimmune disorder may result in:

A person may have more than one autoimmune disorder at the same time. Common autoimmune disorders include:

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Track: 11Costimmulatory pathways in multiple sclerosis

Costimulatory moleculescan be categorized based either on their functional attributes or on their structure. The costimulatory molecules discussed in this review will be divided into (1)positive costimulatory pathways:promoting T cell activation, survival and/or differentiation; (2)negative costimulatory pathways:antagonizing TCR signalling and suppressing T cell activation; (3) as third group we will discuss themembers of the TIM family, a rather new family of cell surface molecules involved in the regulation of T cell differentiation and Treg function.Costimulatory pathways have a critical role in the regulation of alloreactivity. A complex network of positive and negative pathways regulates T cell responses. Blocking costimulation improves allograft survival in rodents and non-human primates. The costimulation blocker belatacept is being developed asimmunosuppressivedruginrenal transplantation.

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Track: 12Autoimmunity and Therapathies

Autoimmunityis the system ofimmuneresponsesof an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases.Autoimmune diseasesoccur when there is progression from benign autoimmunity to pathogenic autoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Current treatments for allergic and autoimmune disease treat disease symptoms or depend on non-specific immune suppression. Treatment would be improved greatly by targeting the fundamental cause of the disease, that is the loss of tolerance to an otherwise innocuous antigen in allergy or self-antigen in autoimmune disease (AID). Much has been learned about the mechanisms of peripheral tolerance in recent years. We now appreciate that antigen presenting cells (APC) may be either immunogenic or tolerogenic, depending on their location, environmental cues and activation state

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Track: 13DiagnosticImmunology

Diagnostic Immunology. Immunoassays are laboratory techniques based on the detection of antibody production in response to foreign antigens. Antibodies, part of the humoral immune response, are involved in pathogen detection and neutralization.

Diagnostic immunology has considerably advanced due to the development of automated methods.New technology takes into account saving samples, reagents, and reducing cost.The future of diagnosticimmunologyfaces challenges in the vaccination field for protection against HIV and asanti-cancer therapy. Modern immunology relies heavily on the use of antibodies as highly specific laboratory reagents. The diagnosis of infectious diseases, the successful outcome of transfusions and transplantations, and the availability of biochemical and hematologic assays with extraordinary specificity and sensitivity capabilities all attest to the value of antibody detection.Immunologic methods are used in the treatment and prevention ofinfectious diseasesand in the large number of immune-mediated diseases. Advances in diagnostic immunology are largely driven by instrumentation, automation, and the implementation of less complex and more standardized procedures.

Examples of such processes are as follows:

These methods have facilitated the performance of tests and have greatly expanded the information that can be developed by a clinical laboratory. The tests are now used for clinical diagnosis and the monitoring of therapies and patient responses. Immunology is a relatively young science and there is still so much to discover. Immunologists work in many different disease areas today that include allergy, autoimmunity, immunodeficiency, transplantation, and cancer.

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Track: 14Allergy and Therapathies

Although medications available for allergy are usually very effective, they do not cure people of allergies. Allergenimmunotherapyis the closest thing we have for a "cure" for allergy, reducing the severity of symptoms and the need for medication for many allergy sufferers. Allergen immunotherapy involves the regular administration of gradually increasing doses of allergen extracts over a period of years. Immunotherapy can be given to patients as an injection or as drops or tablets under the tongue (sublingual).Allergen immunotherapy changes the way the immune system reacts to allergens, by switching off allergy. The end result is that you become immune to the allergens, so that you can tolerate them with fewer or no symptoms. Allergen immunotherapy is not, however, a quick fix form of treatment. Those agreeing to allergen immunotherapy need to be committed to 3-5 years of treatment for it to work, and to cooperate with your doctor to minimize the frequency of side effects.Allergen immunotherapyis usually recommended for the treatment of potentially life threatening allergic reactions to stinging insects. Published data on allergen immunotherapy injections shows that venom immunotherapy can reduce the risk of a severe reaction in adults from around 60 % per sting, down to less than 10%. In Australia and New Zealand,venom immunotherapyis currently available for bee and wasp allergy. Jack Jumper Ant immunotherapy is available in Tasmania for Tasmanian residents. Allergen immunotherapy is often recommended for treatment ofallergic rhinitis

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Track: 15Technological Innovations inImmunology

Immunology is the branch of biomedical sciences concerned with all aspects of the immune system in all multicellular organisms. Immunology deals with physiological functioning of the immune system in states of both health and disease as well as malfunctions of the immune system in immunological disorders like allergies, hypersensitivities, immune deficiency, transplant rejection andautoimmune disorders.

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Track:16Antigen Processing

Antigen processingis an immunologicalprocessthat prepares antigensfor presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage ofantigenpresentation pathways. The process by which antigen-presenting cells digest proteins from inside or outside the cell and display the resulting antigenic peptide fragments on cell surface MHC molecules for recognition by T cells is central to the body's ability to detect signs of infection or abnormal cell growth. As such, understanding the processes and mechanisms of antigen processing and presentation provides us with crucial insights necessary for the design ofvaccines and therapeutic strategiesto bolster T-cell responses.

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Track: 17Immunoinformatics and Systems Immunology

Immunoinformaticsis a branch ofbioinformaticsdealing with in silico analysis and modelling of immunological data and problems Immunoinformatics includes the study and design of algorithms for mapping potential B- andT-cell epitopes, which lessens the time and cost required for laboratory analysis of pathogen gene products. Using this information, an immunologist can explore the potential binding sites, which, in turn, leads to the development of newvaccines. This methodology is termed reversevaccinology and it analyses the pathogen genome to identify potential antigenic proteins.This is advantageous because conventional methods need to cultivate pathogen and then extract its antigenic proteins. Although pathogens grow fast, extraction of their proteins and then testing of those proteins on a large scale is expensive and time consuming. Immunoinformatics is capable of identifying virulence genes and surface-associated proteins.

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Track: 18Rheumatology

Rheumatology represents a subspecialty in internal medicine and pediatrics, which is devoted to adequate diagnosis andtherapy of rheumatic diseases(including clinical problems in joints, soft tissues, heritable connective tissue disorders, vasculitis and autoimmune diseases). This field is multidisciplinary in nature, which means it relies on close relationships with other medical specialties.The specialty of rheumatology has undergone a myriad of noteworthy advances in recent years, especially if we consider the development of state-of-the-art biological drugs with novel targets, made possible by rapid advances in the basic science of musculoskeletal diseases and improved imaging techniques.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 19Nutritional Immunology

Nutritional immunologyis an emerging discipline that evolved with the study of the detrimental effect of malnutrition on the immune system. The clinical and public health importance of nutritional immunology is also receiving attention. Immune system dysfunctions that result from malnutrition are, in fact, NutritionallyAcquired Immune Deficiency Syndromes(NAIDS). NAIDS afflicts millions of people in the Third World, as well as thousands in modern centers, i.e., patients with cachexia secondary to serious disease, neoplasia or trauma. The human immune system functions to protect the body against foreign pathogens and thereby preventing infection and disease. Optimal functioning of the immune system, both innate and adaptive immunity, is strongly influenced by an individuals nutritional status, with malnutrition being the most common cause of immunodeficiency in the world. Nutrient deficiencies result in immunosuppression and dysregulation of the immune response including impairment of phagocyte function and cytokine production, as well as adversely affecting aspects of humoral and cell-mediated immunity. Such alterations in immune function and the resulting inflammation are not only associated with infection, but also with the development of chronic diseases including cancer, autoimmune disease, osteoporosis, disorders of the endocrine system andcardiovascular disease.

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8 - OMICS International Conference

Hematopoietic stem cell transplantation – Wikipedia

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood.[1][2] It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).[1][2] It is a medical procedure in the field of hematology, most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.[2] In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.[2]

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer, such as autoimmune diseases.[3][4]

Indications for stem cell transplantation are as follows:

Many recipients of HSCTs are multiple myeloma[5] or leukemia patients[6] who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia[7] who have lost their stem cells after birth. Other conditions[8] treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's sarcoma, desmoplastic small round cell tumor, chronic granulomatous disease and Hodgkin's disease. More recently non-myeloablative, "mini transplant(microtransplantation)," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.

In 2006 a total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57 percent) were autologous and 21,516 (43 percent) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (54.5 percent) and leukemias (33.8 percent), and the majority took place in either Europe (48 percent) or the Americas (36 percent).[9]

In 2014, according to the World Marrow Donor Association, stem cell products provided for unrelated transplantation worldwide had increased to 20,604 (4,149 bone marrow donations, 12,506 peripheral blood stem cell donations, and 3,949 cord blood units).[10]

Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient's bone marrow's ability to grow new blood cells). The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (and graft-versus-host disease is impossible) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma.[11]

However, for other cancers such as acute myeloid leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions.[12] Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, as of 2009[update] it was premature to speculate whether these experiments will lead to effective treatments for diabetes.[13]

Allogeneics HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the HLA gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match.[14] A "savior sibling" may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.[15][16][17]

A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.

Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.[18]

As of 2013[update], there were at least two commercialized allogeneic cell therapies, Prochymal and Cartistem.[19]

To limit the risks of transplanted stem cell rejection or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA) as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.

In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.

Peripheral blood stem cells[20] are now the most common source of stem cells for HSCT. They are collected from the blood through a process known as apheresis. The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor. The peripheral stem cell yield is boosted with daily subcutaneous injections of Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.

It is also possible to extract stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.

Umbilical cord blood is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an Umbilical Cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow cord blood transplants to be used in adults.

Cord blood can be harvested from the Umbilical Cord of a child being born after preimplantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.

Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods without damaging too many cells. This is a necessity with autologous HSC because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of allogeneic transplants, fresh HSC are preferred in order to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a cord blood bank because it is only obtainable at the time of childbirth. To cryopreserve HSC, a preservative, DMSO, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer, which typically uses liquid nitrogen.

The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide with total body irradiation is conventionally employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system. The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. However, in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect.[21]Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.

A newer treatment approach, non-myeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone marrow cells of the recipient.[22]:320321 Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse.[23][24] Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants.[25] This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space.

Decreasing doses of immunosuppressive therapy then allows donor T-cells to eradicate the remaining recipient HSC and to induce the graft versus tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents.

Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality and therefore allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable.[22][24]

After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and re-initiate the immune system. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart, liver, and muscle, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon[citation needed].

HSCT is associated with a high treatment-related mortality in the recipient (1 percent or higher)[citation needed], which limits its use to conditions that are themselves life-threatening. Major complications are veno-occlusive disease, mucositis, infections (sepsis), graft-versus-host disease and the development of new malignancies.

Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics. However, antiviral medications, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic infection in seropositive patients.[26] The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.

Severe liver injury can result from hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe cases of SOS are associated with a high mortality rate. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by facilitating the flow of bile.

The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack of the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is aptly named graft-versus-host disease because bone marrow transplantation is the only transplant procedure in which the transplanted cells must accept the body rather than the body accepting the new cells.[27]

Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin, intestine, or the liver. High-dose corticosteroids such as prednisone are a standard treatment; however this immuno-suppressive treatment often leads to deadly infections. Chronic graft-versus-host disease may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma; it may cause functional disability and require prolonged immunosuppressive therapy. Graft-versus-host disease is usually mediated by T cells, which react to foreign peptides presented on the MHC of the host.[citation needed]

Graft versus tumor effect (GVT) or "graft versus leukemia" effect is the beneficial aspect of the Graft-versus-Host phenomenon. For example, HSCT patients with either acute, or in particular chronic, graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse.[28][29] This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immuno-suppressive regimens.

Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.[30]

If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells (Donor lymphocyte infusion).[30]

Patients after HSCT are at a higher risk for oral carcinoma. Post-HSCT oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.[31]

Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HSCT) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived.[15][16] In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.[32]

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al.,[33] using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.[34]) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF). G-CSF drugs include filgrastim (Neupogen, Neulasta), and lenograstim (Graslopin).

Filgrastim is typically dosed in the 10 microgram/kg level for 45 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Adult respiratory distress syndrome (ARDS), alveolar hemorrage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300).[35][36][37] In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.[37]

The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors.[36] There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.[38]

Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16 percent of women and 4 percent of men. Adverse reactions during apheresis were experienced in 20 percent of women and 8 percent of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.[37]

A study involving 2408 donors (1860 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80 percent of donors by day 4 post-injection.[37] This pain responded to acetaminophen or ibuprofen in 65 percent of donors and was characterized as mild to moderate in 80 percent of donors and severe in 10 percent.[37] Bone pain receded post-donation to 26 percent of patients 2 days post-donation, 6 percent of patients one week post-donation, and

In one metastudy that incorporated data from 377 donors, 44 percent of patients reported having adverse side effects after peripheral blood HSCT.[38] Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.[38]

A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6 percent), although none of these events were fatal.[37] Donors were not observed to have higher than normal rates of cancer with up to 48 years of follow up.[37] One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500.[36] This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population, with only 15 reported cases within 4 years.[36]

Georges Math, a French oncologist, performed the first European bone marrow transplant in November 1958 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a criticality accident at the Vina Nuclear Institute, but all of these transplants were rejected.[39][40][41][42][43] Math later pioneered the use of bone marrow transplants in the treatment of leukemia.[43]

Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease.[44]

The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968.[45] In 1975, John Kersey, M.D., also of the University of Minnesota, performed the first successful bone marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor.[46]

At the end of 2012, 20.2 million people had registered their willingness to be a bone marrow donor with one of the 67 registries from 49 countries participating in Bone Marrow Donors Worldwide. 17.9 million of these registered donors had been ABDR typed, allowing easy matching. A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating. The highest total number of bone marrow donors registered were those from the USA (8.0 million), and the highest number per capita were those from Cyprus (15.4 percent of the population).[47]

Within the United States, racial minority groups are the least likely to be registered and therefore the least likely to find a potentially life-saving match. In 1990, only six African-Americans were able to find a bone marrow match, and all six had common European genetic signatures.[48]

Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in South Africa, and a new program is beginning in Nigeria.[48] Many people belonging to different races are requested to donate as there is a shortage of donors in African, Mixed race, Latino, Aboriginal, and many other communities.

In 2007, a team of doctors in Berlin, Germany, including Gero Htter, performed a stem cell transplant for leukemia patient Timothy Ray Brown, who was also HIV-positive.[49] From 60 matching donors, they selected a [CCR5]-32 homozygous individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations.[50][51] The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues.[52] Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case.[53] Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease and leukoencephalopathy) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.[54][55]

In 2012, Daniel Kuritzkes reported results of two stem cell transplants in patients with HIV. They did not, however, use donors with the 32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified CD4 T cells using a sensitive culture method (less than 3 copies/mL). However, the virus was once again detected in both patients some time after the discontinuation of therapy.[56]

Since McAllister's 1997 report on a patient with multiple sclerosis (MS) who received a bone marrow transplant for CML,[57] over 600 reports have been published describing HSCTs performed primarily for MS.[58] These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" that have aggressive highly active MS, "in the absence of chronic treatment with disease-modifying agents".[58]

Clincs performing HSCT includes Northwestern University and Karolinska University Hospital.

See the article here:
Hematopoietic stem cell transplantation - Wikipedia

Bone marrow Journals | Peer Reviewed| High Impact Articles …

The journal is using Editorial Manager System for quality in review process. Editorial Manager is an online manuscript submission, review and tracking system. Review processing is performed by the editorial board members of Journal of Bone Research or outside experts; at least two independent reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission/review/revise/publish process.

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Osteoimmunology is a new research field that investigates the interaction of the immune system with the skeleton. Osteoimmunology has contributed significantly to the understanding of joint destruction in rheumatoid arthritis and other forms of arthropathiesOsteoimmunology has also allowed an improvement in our knowledge of the structure-sparing effects of antirheumatic drug therapy.

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Pain is complex, so there are many treatment options -- medications, therapies, and mind-body techniques. Medications, mind-body techniques, and acupuncture can help relieve chronic pain. Learn about your options.A pain clinic is a health care facility that focuses on the diagnosis and management of chronic pain.Research shows that acupuncture and other nonmedical treatments can provide pain relief.

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Radiation therapy uses high-energy rays or particles to kill cancer cells. External beam radiation therapy uses radiation delivered from outside the body that is focused on the cancer. This is the type of radiation therapy that has been tried as a treatment for bone cancer. Often radiation is used to treat bone cancers that are unresectable (they cannot be completely removed by surgery). Radiation may also be used after surgery if cancer cells were present in the edges of the removed tissueIf the cancer comes back after treatment, radiation can help control symptoms like pain and swelling.

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Future prospects for nanotechnology and biomaterials in medical applications appear to be excellent.Bone is a nanocomposite material comprised of hierarchically arranged collagen fibrils, hydroxyapatite and proteoglycans in the nanometer scaleCells are accustomed to interact with nanostructures, thus providing the cells with a natural bone-like environment that potentially enhance bone tissue regeneration/repair.In this direction, nanotechnology provides opportunities to fabricate as well as explore novel properties and phenomena of functional materials, devices, and systems at the nanometer-length scale.

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The musculoskeletal system provides form, support, stability, and movement to the body. It is made up of the bones of the skeleton, muscles, cartilage, tendons, ligaments, joints, and other connective tissue that supports and binds tissues and organs together.

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Bone marrow – Wikipedia

Bone marrow is the flexible tissue in the interior of bones. In humans, red blood cells are produced by cores of bone marrow in the heads of long bones in a process known as hematopoiesis.[2] On average, bone marrow constitutes 4% of the total body mass of humans; in an adult having 65 kilograms of mass (143 lbs), bone marrow typically accounts for approximately 2.6 kilograms (5.7lb). The hematopoietic component of bone marrow produces approximately 500 billion blood cells per day, which use the bone marrow vasculature as a conduit to the body's systemic circulation.[3] Bone marrow is also a key component of the lymphatic system, producing the lymphocytes that support the body's immune system.[4]

Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Additionally, bone marrow stem cells have been successfully transformed into functional neural cells,[5] and can also potentially be used to treat illnesses such as inflammatory bowel disease.[6]

The two types of bone marrow are "red marrow" (Latin: medulla ossium rubra), which consists mainly of hematopoietic tissue, and "yellow marrow" (Latin: medulla ossium flava), which is mainly made up of fat cells. Red blood cells, platelets, and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type; only around half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous ("spongy") material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of short bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.

The stroma of the bone marrow is all tissue not directly involved in the marrow's primary function of hematopoiesis.[2] Yellow bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

In addition, the bone marrow contains hematopoietic stem cells, which give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes).[7]

The bone marrow stroma contains mesenchymal stem cells (MSCs),[7] also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islets cells.

The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium.[9]Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.

The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells.[4] The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.

Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.[7]

Animal bone marrow has been used in cuisine worldwide for millennia, such as the famed Milanese Ossobuco.[citation needed]

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells.[10] Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.

To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia.[11]

On CT and plain film, marrow change can be seen indirectly by assessing change to the adjacent ossified bone. Assessment with MRI is usually more sensitive and specific for pathology, particularly for hematologic malignancies like leukemia and lymphoma. These are difficult to distinguish from the red marrow hyperplasia of hematopoiesis, as can occur with tobacco smoking, chronically anemic disease states like sickle cell anemia or beta thalassemia, medications such as granulocyte colony-stimulating factors, or during recovery from chronic nutritional anemias or therapeutic bone marrow suppression.[12] On MRI, the marrow signal is not supposed to be brighter than the adjacent intervertebral disc on T1 weighted images, either in the coronal or sagittal plane, where they can be assessed immediately adjacent to one another.[13] Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging,[14] though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process.[15]

Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.

The ratio between myeloid series and erythroid cells is relevant to bone marrow function, and also to diseases of the bone marrow and peripheral blood, such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of thalassemia.[16]

In a bone marrow transplant, hematopoietic stem cells are removed from a person and infused into another person (allogenic) or into the same person at a later time (autologous). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system.[17]

Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses,[5] and can also potentially be used for the treatment of other illnesses, such as inflammatory bowel disease.[6] In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat HIV in conjunction with antiretroviral drugs;[18][19] however, it was later found that HIV remained in the bodies of the test subjects.[20]

The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia. The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 12 days of recovery in the hospital.[21]

Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood.[22] An intravenous catheter is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the sternum, while the tibia is often used when taking samples from infants.[11] In newborns, stem cells may be retrieved from the umbilical cord.[23]

The earliest fossilised evidence of bone marrow was discovered in 2014 in Eusthenopteron, a lobe-finned fish which lived during the Devonian period approximately 370 million years ago.[24] Scientists from Uppsala University and the European Synchrotron Radiation Facility used X-ray synchrotron microtomography to study the fossilised interior of the skeleton's humerus, finding organised tubular structures akin to modern vertebrate bone marrow.[24]Eusthenopteron is closely related to the early tetrapods, which ultimately evolved into the land-dwelling mammals and lizards of the present day.[24]

Excerpt from:
Bone marrow - Wikipedia

Bone Marrow (Hematopoietic) Stem Cells | stemcells.nih.gov

by Jos Domen*, Amy Wagers** and Irving L. Weissman***

Blood and the system that forms it, known as the hematopoietic system, consist of many cell types with specialized functions (see Figure 2.1). Red blood cells (erythrocytes) carry oxygen to the tissues. Platelets (derived from megakaryocytes) help prevent bleeding. Granulocytes (neutrophils, basophils and eosinophils) and macrophages (collectively known as myeloid cells) fight infections from bacteria, fungi, and other parasites such as nematodes (ubiquitous small worms). Some of these cells are also involved in tissue and bone remodeling and removal of dead cells. B-lymphocytes produce antibodies, while T-lymphocytes can directly kill or isolate by inflammation cells recognized as foreign to the body, including many virus-infected cells and cancer cells. Many blood cells are short-lived and need to be replenished continuously; the average human requires approximately one hundred billion new hematopoietic cells each day. The continued production of these cells depends directly on the presence of Hematopoietic Stem Cells (HSCs), the ultimate, and only, source of all these cells.

Figure 2.1. Hematopoietic and stromal cell differentiation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

The search for stem cells began in the aftermath of the bombings in Hiroshima and Nagasaki in 1945. Those who died over a prolonged period from lower doses of radiation had compromised hematopoietic systems that could not regenerate either sufficient white blood cells to protect against otherwise nonpathogenic infections or enough platelets to clot their blood. Higher doses of radiation also killed the stem cells of the intestinal tract, resulting in more rapid death. Later, it was demonstrated that mice that were given doses of whole body X-irradiation developed the same radiation syndromes; at the minimal lethal dose, the mice died from hematopoietic failure approximately two weeks after radiation exposure.1 Significantly, however, shielding a single bone or the spleen from radiation prevented this irradiation syndrome. Soon thereafter, using inbred strains of mice, scientists showed that whole-body-irradiated mice could be rescued from otherwise fatal hematopoietic failure by injection of suspensions of cells from blood-forming organs such as the bone marrow.2 In 1956, three laboratories demonstrated that the injected bone marrow cells directly regenerated the blood-forming system, rather than releasing factors that caused the recipients' cells to repair irradiation damage.35 To date, the only known treatment for hematopoietic failure following whole body irradiation is transplantation of bone marrow cells or HSCs to regenerate the blood-forming system in the host organisms.6,7

The hematopoietic system is not only destroyed by the lowest doses of lethal X-irradiation (it is the most sensitive of the affected vital organs), but also by chemotherapeutic agents that kill dividing cells. By the 1960s, physicians who sought to treat cancer that had spread (metastasized) beyond the primary cancer site attempted to take advantage of the fact that a large fraction of cancer cells are undergoing cell division at any given point in time. They began using agents (e.g., chemical and X-irradiation) that kill dividing cells to attempt to kill the cancer cells. This required the development of a quantitative assessment of damage to the cancer cells compared that inflicted on normal cells. Till and McCulloch began to assess quantitatively the radiation sensitivity of one normal cell type, the bone marrow cells used in transplantation, as it exists in the body. They found that, at sub-radioprotective doses of bone marrow cells, mice that died 1015 days after irradiation developed colonies of myeloid and erythroid cells (see Figure 2.1 for an example) in their spleens. These colonies correlated directly in number with the number of bone marrow cells originally injected (approximately 1 colony per 7,000 bone marrow cells injected).8 To test whether these colonies of blood cells derived from single precursor cells, they pre-irradiated the bone marrow donors with low doses of irradiation that would induce unique chromosome breaks in most hematopoietic cells but allow some cells to survive. Surviving cells displayed radiation-induced and repaired chromosomal breaks that marked each clonogenic (colony-initiating) hematopoietic cell.9 The researchers discovered that all dividing cells within a single spleen colony, which contained different types of blood cells, contained the same unique chromosomal marker. Each colony displayed its own unique chromosomal marker, seen in its dividing cells.9 Furthermore, when cells from a single spleen colony were re-injected into a second set of lethally-irradiated mice, donor-derived spleen colonies that contained the same unique chromosomal marker were often observed, indicating that these colonies had been regenerated from the same, single cell that had generated the first colony. Rarely, these colonies contained sufficient numbers of regenerative cells both to radioprotect secondary recipients (e.g., to prevent their deaths from radiation-induced blood cell loss) and to give rise to lymphocytes and myeloerythroid cells that bore markers of the donor-injected cells.10,11 These genetic marking experiments established the fact that cells that can both self-renew and generate most (if not all) of the cell populations in the blood must exist in bone marrow. At the time, such cells were called pluripotent HSCs, a term later modified to multipotent HSCs.12,13 However, identifying stem cells in retrospect by analysis of randomly chromosome-marked cells is not the same as being able to isolate pure populations of HSCs for study or clinical use.

Achieving this goal requires markers that uniquely define HSCs. Interestingly, the development of these markers, discussed below, has revealed that most of the early spleen colonies visible 8 to 10 days after injection, as well as many of the later colonies, visible at least 12 days after injection, are actually derived from progenitors rather than from HSCs. Spleen colonies formed by HSCs are relatively rare and tend to be present among the later colonies.14,15 However, these findings do not detract from Till and McCulloch's seminal experiments to identify HSCs and define these unique cells by their capacities for self-renewal and multilineage differentiation.

While much of the original work was, and continues to be, performed in murine model systems, strides have been made to develop assays to study human HSCs. The development of Fluorescence Activated Cell Sorting (FACS) has been crucial for this field (see Figure 2.2). This technique enables the recognition and quantification of small numbers of cells in large mixed populations. More importantly, FACS-based cell sorting allows these rare cells (1 in 2000 to less than 1 in 10,000) to be purified, resulting in preparations of near 100% purity. This capability enables the testing of these cells in various assays.

Figure 2.2. Enrichment and purification methods for hematopoietic stem cells. Upper panels illustrate column-based magnetic enrichment. In this method, the cells of interest are labeled with very small iron particles (A). These particles are bound to antibodies that only recognize specific cells. The cell suspension is then passed over a column through a strong magnetic field which retains the cells with the iron particles (B). Other cells flow through and are collected as the depleted negative fraction. The magnet is removed, and the retained cells are collected in a separate tube as the positive or enriched fraction (C). Magnetic enrichment devices exist both as small research instruments and large closed-system clinical instruments.

Lower panels illustrate Fluorescence Activated Cell Sorting (FACS). In this setting, the cell mixture is labeled with fluorescent markers that emit light of different colors after being activated by light from a laser. Each of these fluorescent markers is attached to a different monoclonal antibody that recognizes specific sets of cells (D). The cells are then passed one by one in a very tight stream through a laser beam (blue in the figure) in front of detectors (E) that determine which colors fluoresce in response to the laser. The results can be displayed in a FACS-plot (F). FACS-plots (see figures 3 and 4 for examples) typically show fluorescence levels per cell as dots or probability fields. In the example, four groups can be distinguished: Unstained, red-only, green-only, and red-green double labeling. Each of these groups, e.g., green fluorescence-only, can be sorted to very high purity. The actual sorting happens by breaking the stream shown in (E) into tiny droplets, each containing 1 cell, that then can be sorted using electric charges to move the drops. Modern FACS machines use three different lasers (that can activate different set of fluorochromes), to distinguish up to 8 to 12 different fluorescence colors and sort 4 separate populations, all simultaneously.

Magnetic enrichment can process very large samples (billions of cells) in one run, but the resulting cell preparation is enriched for only one parameter (e.g., CD34) and is not pure. Significant levels of contaminants (such as T-cells or tumor cells) remain present. FACS results in very pure cell populations that can be selected for several parameters simultaneously (e.g., Linneg, CD34pos, CD90pos), but it is more time consuming (10,000 to 50,000 cells can be sorted per second) and requires expensive instrumentation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

Assays have been developed to characterize hematopoietic stem and progenitor cells in vitro and in vivo (Figure 2.3).16,17In vivo assays that are used to study HSCs include Till and McCulloch's classical spleen colony forming (CFU-S) assay,8 which measures the ability of HSC (as well as blood-forming progenitor cells) to form large colonies in the spleens of lethally irradiated mice. Its main advantage (and limitation) is the short-term nature of the assay (now typically 12 days). However, the assays that truly define HSCs are reconstitution assays.16,18 Mice that have been quot;preconditionedquot; by lethal irradiation to accept new HSCs are injected with purified HSCs or mixed populations containing HSCs, which will repopulate the hematopoietic systems of the host mice for the life of the animal. These assays typically use different types of markers to distinguish host and donor-derived cells.

For example, allelic assays distinguish different versions of a particular gene, either by direct analysis of dna or of the proteins expressed by these alleles. These proteins may be cell-surface proteins that are recognized by specific monoclonal antibodies that can distinguish between the variants (e.g., CD45 in Figure 2.3) or cellular proteins that may be recognized through methods such as gel-based analysis. Other assays take advantage of the fact that male cells can be detected in a female host by detecting the male-cell-specific Y-chromosome by molecular assays (e.g., polymerase chain reaction, or PCR).

Figure 2.3. Assays used to detect hematopoietic stem cells. The tissue culture assays, which are used frequently to test human cells, include the ability of the cells to be tested to grow as quot;cobblestonesquot; (the dark cells in the picture) for 5 to 7 weeks in culture. The Long Term Culture-Initiating Cell assay measures whether hematopoietic progenitor cells (capable of forming colonies in secondary assays, as shown in the picture) are still present after 5 to 7 weeks of culture.

In vivo assays in mice include the CFU-S assay, the original stem cell assay discussed in the introduction. The most stringent hematopoietic stem cell assay involves looking for the long-term presence of donor-derived cells in a reconstituted host. The example shows host-donor recognition by antibodies that recognize two different mouse alleles of CD45, a marker present on nearly all blood cells. CD45 is also a good marker for distinguishing human blood cells from mouse blood cells when testing human cells in immunocompromised mice such as NOD/SCID. Other methods such as pcr-markers, chromosomal markers, and enzyme markers can also be used to distinguish host and donor cells.

Small numbers of HSCs (as few as one cell in mouse experiments) can be assayed using competitive reconstitutions, in which a small amount of host-type bone marrow cells (enough to radioprotect the host and thus ensure survival) is mixed in with the donor-HSC population. To establish long-term reconstitutions in mouse models, the mice are followed for at least 4 months after receiving the HSCs. Serial reconstitution, in which the bone marrow from a previously-irradiated and reconstituted mouse becomes the HSC source for a second irradiated mouse, extends the potential of this assay to test lifespan and expansion limits of HSCs. Unfortunately, the serial transfer assay measures both the lifespan and the transplantability of the stem cells. The transplantability may be altered under various conditions, so this assay is not the sine qua non of HSC function. Testing the in vivo activity of human cells is obviously more problematic.

Several experimental models have been developed that allow the testing of human cells in mice. These assays employ immunologically-incompetent mice (mutant mice that cannot mount an immune response against foreign cells) such as SCID1921 or NOD-SCID mice.22,23 Reconstitution can be performed in either the presence or absence of human fetal bone or thymus implants to provide a more natural environment in which the human cells can grow in the mice. Recently NOD/SCID/c-/- mice have been used as improved recipients for human HSCs, capable of complete reconstitution with human lymphocytes, even in the absence of additional human tissues.24 Even more promising has been the use of newborn mice with an impaired immune system (Rag-2-/-C-/-), which results in reproducible production of human B- and T-lymphoid and myeloerythroid cells.25 These assays are clearly more stringent, and thus more informative, but also more difficult than the in vitro HSC assays discussed below. However, they can only assay a fraction of the lifespan under which the cells would usually have to function. Information on the long-term functioning of cells can only be derived from clinical HSC transplantations.

A number of assays have been developed to recognize HSCs in vitro (e.g., in tissue culture). These are especially important when assaying human cells. Since transplantation assays for human cells are limited, cell culture assays often represent the only viable option. In vitro assays for HSCs include Long-Term Culture-Initializing Cell (LTC-IC) assays2628 and Cobble-stone Area Forming Cell (CAFC) assays.29 LTC-IC assays are based on the ability of HSCs, but not more mature progenitor cells, to maintain progenitor cells with clonogenic potential over at least a five-week culture period. CAFC assays measure the ability of HSCs to maintain a specific and easily recognizable way of growing under stromal cells for five to seven weeks after the initial plating. Progenitor cells can only grow in culture in this manner for shorter periods of time.

While initial experiments studied HSC activity in mixed populations, much progress has been made in specifically describing the cells that have HSC activity. A variety of markers have been discovered to help recognize and isolate HSCs. Initial marker efforts focused on cell size, density, and recognition by lectins (carbohydrate-binding proteins derived largely from plants),30 but more recent efforts have focused mainly on cell surface protein markers, as defined by monoclonal antibodies. For mouse HSCs, these markers include panels of 8 to 14 different monoclonal antibodies that recognize cell surface proteins present on differentiated hematopoietic lineages, such as the red blood cell and macrophage lineages (thus, these markers are collectively referred to as quot;Linquot;),13,31 as well as the proteins Sca-1,13,31 CD27,32 CD34,33 CD38,34 CD43,35 CD90.1(Thy-1.1),13,31 CD117(c-Kit),36 AA4.1,37 and MHC class I,30 and CD150.38 Human HSCs have been defined with respect to staining for Lin,39 CD34,40 CD38,41 CD43,35 CD45RO,42 CD45RA,42 CD59,43 CD90,39 CD109,44 CD117,45 CD133,46,47CD166,48 and HLA DR(human).49,50 In addition, metabolic markers/dyes such as rhodamine123 (which stains mitochondria),51 Hoechst33342 (which identifies MDR-type drug efflux activity),52 Pyronin-Y (which stains RNA),53 and BAAA (indicative of aldehyde dehydrogenase enzyme activity)54 have been described. While none of these markers recognizes functional stem cell activity, combinations (typically with 3 to 5 different markers, see examples below) allow for the purification of near-homogenous populations of HSCs. The ability to obtain pure preparations of HSCs, albeit in limited numbers, has greatly facilitated the functional and biochemical characterization of these important cells. However, to date there has been limited impact of these discoveries on clinical practice, as highly purified HSCs have only rarely been used to treat patients (discussed below). The undeniable advantages of using purified cells (e.g., the absence of contaminating tumor cells in autologous transplantations) have been offset by practical difficulties and increased purification costs.

Figure 2.4. Examples of Hematopoietic Stem Cell staining patterns in mouse bone marrow (top) and human mobilized peripheral blood (bottom). The plots on the right show only the cells present in the left blue box. The cells in the right blue box represent HSCs. Stem cells form a rare fraction of the cells present in both cases.

HSC assays, when combined with the ability to purify HSCs, have provided increasingly detailed insight into the cells and the early steps involved in the differentiation process. Several marker combinations have been developed that describe murine HSCs, including [CD117high, CD90.1low, Linneg/low, Sca-1pos],15 [CD90.1low, Linneg, Sca-1pos Rhodamine123low],55 [CD34neg/low, CD117pos, Sca-1pos, Linneg],33 [CD150 pos, CD48neg, CD244neg],38 and quot;side-populationquot; cells using Hoechst-dye.52 Each of these combinations allows purification of HSCs to near-homogeneity. Figure 2.4 shows an example of an antibody combination that can recognize mouse HSCs. Similar strategies have been developed to purify human HSCs, employing markers such as CD34, CD38, Lin, CD90, CD133 and fluorescent substrates for the enzyme, aldehyde dehydrogenase. The use of highly purified human HSCs has been mainly experimental, and clinical use typically employs enrichment for one marker, usually CD34. CD34 enrichment yields a population of cells enriched for HSC and blood progenitor cells but still contains many other cell types. However, limited trials in which highly FACS-purified CD34pos CD90pos HSCs (see Figure 2.4) were used as a source of reconstituting cells have demonstrated that rapid reconstitution of the blood system can reliably be obtained using only HSCs.5658

The purification strategies described above recognize a rare subset of cells. Exact numbers depend on the assay used as well as on the genetic background studied.16 In mouse bone marrow, 1 in 10,000 cells is a hematopoietic stem cell with the ability to support long-term hematopoiesis following transplantation into a suitable host. When short-term stem cells, which have a limited self-renewal capacity, are included in the estimation, the frequency of stem cells in bone marrow increases to 1 in 1,000 to 1 in 2,000 cells in humans and mice. The numbers present in normal blood are at least ten-fold lower than in marrow.

None of the HSC markers currently used is directly linked to an essential HSC function, and consequently, even within a species, markers can differ depending on genetic alleles,59 mouse strains,60 developmental stages,61 and cell activation stages.62,63 Despite this, there is a clear correlation in HSC markers between divergent species such as humans and mice. However, unless the ongoing attempts at defining the complete HSC gene expression patterns will yield usable markers that are linked to essential functions for maintaining the quot;stemnessquot; of the cells,64,65 functional assays will remain necessary to identify HSCs unequivocally.16

More recently, efforts at defining hematopoietic populations by cell surface or other FACS-based markers have been extended to several of the progenitor populations that are derived from HSCs (see Figure 2.5). Progenitors differ from stem cells in that they have a reduced differentiation capacity (they can generate only a subset of the possible lineages) but even more importantly, progenitors lack the ability to self-renew. Thus, they have to be constantly regenerated from the HSC population. However, progenitors do have extensive proliferative potential and can typically generate large numbers of mature cells. Among the progenitors defined in mice and humans are the Common Lymphoid Progenitor (CLP),66,67 which in adults has the potential to generate all of the lymphoid but not myeloerythroid cells, and a Common Myeloid Progenitor (CMP), which has the potential to generate all of the mature myeloerythroid, but not lymphoid, cells.68,69 While beyond the scope of this overview, hematopoietic progenitors have clinical potential and will likely see clinical use.70,71

Figure 2.5. Relationship between several of the characterized hematopoietic stem cells and early progenitor cells. Differentiation is indicated by colors; the more intense the color, the more mature the cells. Surface marker distinctions are subtle between these early cell populations, yet they have clearly distinct potentials. Stem cells can choose between self-renewal and differentiation. Progenitors can expand temporarily but always continue to differentiate (other than in certain leukemias). The mature lymphoid (T-cells, B-cells, and Natural Killer cells) and myeloerythroid cells (granulocytes, macrophages, red blood cells, and platelets) that are produced by these stem and progenitor cells are shown in more detail in Figure 2.1.

HSCs have a number of unique properties, the combination of which defines them as such.16 Among the core properties are the ability to choose between self-renewal (remain a stem cell after cell division) or differentiation (start the path towards becoming a mature hematopoietic cell). In addition, HSCs migrate in regulated fashion and are subject to regulation by apoptosis (programmed cell death). The balance between these activities determines the number of stem cells that are present in the body.

One essential feature of HSCs is the ability to self-renew, that is, to make copies with the same or very similar potential. This is an essential property because more differentiated cells, such as hematopoietic progenitors, cannot do this, even though most progenitors can expand significantly during a limited period of time after being generated. However, for continued production of the many (and often short-lived) mature blood cells, the continued presence of stem cells is essential. While it has not been established that adult HSCs can self-renew indefinitely (this would be difficult to prove experimentally), it is clear from serial transplantation experiments that they can produce enough cells to last several (at least four to five) lifetimes in mice. It is still unclear which key signals allow self-renewal. One link that has been noted is telomerase, the enzyme necessary for maintaining telomeres, the DNA regions at the end of chromosomes that protect them from accumulating damage due to DNA replication. Expression of telomerase is associated with self-renewal activity.72 However, while absence of telomerase reduces the self-renewal capacity of mouse HSCs, forced expression is not sufficient to enable HSCs to be transplanted indefinitely; other barriers must exist.73,74

It has proven surprisingly difficult to grow HSCs in culture despite their ability to self-renew. Expansion in culture is routine with many other cells, including neural stem cells and ES cells. The lack of this capacity for HSCs severely limits their application, because the number of HSCs that can be isolated from mobilized blood, umbilical cord blood, or bone marrow restricts the full application of HSC transplantation in man (whether in the treatment of nuclear radiation exposure or transplantation in the treatment of blood cell cancers or genetic diseases of the blood or blood-forming system). Engraftment periods of 50 days or more were standard when limited numbers of bone marrow or umbilical cord blood cells were used in a transplant setting, reflecting the low level of HSCs found in these native tissues. Attempts to expand HSCs in tissue culture with known stem-cell stimulators, such as the cytokines stem cell factor/steel factor (KitL), thrombopoietin (TPO), interleukins 1, 3, 6, 11, plus or minus the myeloerythroid cytokines GM-CSF, G-CSF, M-CSF, and erythropoietin have never resulted in a significant expansion of HSCs.16,75 Rather, these compounds induce many HSCs into cell divisions that are always accompanied by cellular differentiation.76 Yet many experiments demonstrate that the transplantation of a single or a few HSCs into an animal results in a 100,000-fold or greater expansion in the number of HSCs at the steady state while simultaneously generating daughter cells that permitted the regeneration of the full blood-forming system.7780 Thus, we do not know the factors necessary to regenerate HSCs by self-renewing cell divisions. By investigating genes transcribed in purified mouse LT-HSCs, investigators have found that these cells contain expressed elements of the Wnt/fzd/beta-catenin signaling pathway, which enables mouse HSCs to undergo self-renewing cell divisions.81,82 Overexpression of several other proteins, including HoxB48386 and HoxA987 has also been reported to achieve this. Other signaling pathways that are under investigation include Notch and Sonic hedgehog.75 Among the intracellular proteins thought to be essential for maintaining the quot;stem cellquot; state are Polycomb group genes, including Bmi-1.88 Other genes, such as c-Myc and JunB have also been shown to play a role in this process.89,90Much remains to be discovered, including the identity of the stimuli that govern self-renewal in vivo, as well as the composition of the environment (the stem cell quot;nichequot;) that provides these stimuli.91 The recent identification of osteoblasts, a cell type known to be involved in bone formation, as a critical component of this environment92,93 will help to focus this search. For instance, signaling by Angiopoietin-1 on osteoblasts to Tie-2 receptors on HSCs has recently been suggested to regulate stem cell quiescence (the lack of cell division).94 It is critical to discover which pathways operate in the expansion of human HSCs to take advantage of these pathways to improve hematopoietic transplantation.

Differentiation into progenitors and mature cells that fulfill the functions performed by the hematopoietic system is not a unique HSC property, but, together with the option to self-renew, defines the core function of HSCs. Differentiation is driven and guided by an intricate network of growth factors and cytokines. As discussed earlier, differentiation, rather than self-renewal, seems to be the default outcome for HSCs when stimulated by many of the factors to which they have been shown to respond. It appears that, once they commit to differentiation, HSCs cannot revert to a self-renewing state. Thus, specific signals, provided by specific factors, seem to be needed to maintain HSCs. This strict regulation may reflect the proliferative potential present in HSCs, deregulation of which could easily result in malignant diseases such as leukemia or lymphoma.

Migration of HSCs occurs at specific times during development (i.e., seeding of fetal liver, spleen and eventually, bone marrow) and under certain conditions (e.g., cytokine-induced mobilization) later in life. The latter has proven clinically useful as a strategy to enhance normal HSC proliferation and migration, and the optimal mobilization regimen for HSCs currently used in the clinic is to treat the stem cell donor with a drug such as cytoxan, which kills most of his or her dividing cells. Normally, only about 8% of LT-HSCs enter the cell cycle per day,95,96 so HSCs are not significantly affected by a short treatment with cytoxan. However, most of the downstream blood progenitors are actively dividing,66,68 and their numbers are therefore greatly depleted by this dose, creating a demand for a regenerated blood-forming system. Empirically, cytokines or growth factors such as G-CSF and KitL can increase the number of HSCs in the blood, especially if administered for several days following a cytoxan pulse. The optimized protocol of cytoxan plus G-CSF results in several self-renewing cell divisions for each resident LT-HSC in mouse bone marrow, expanding the number of HSCs 12- to 15-fold within two to three days.97 Then, up to one-half of the daughter cells of self-renewing dividing LT-HSCs (estimated to be up to 105 per mouse per day98) leave the bone marrow, enter the blood, and within minutes engraft other hematopoietic sites, including bone marrow, spleen, and liver.98 These migrating cells can and do enter empty hematopoietic niches elsewhere in the bone marrow and provide sustained hematopoietic stem cell self-renewal and hematopoiesis.98,99 It is assumed that this property of mobilization of HSCs is highly conserved in evolution (it has been shown in mouse, dog and humans) and presumably results from contact with natural cell-killing agents in the environment, after which regeneration of hematopoiesis requires restoring empty HSC niches. This means that functional, transplantable HSCs course through every tissue of the body in large numbers every day in normal individuals.

Apoptosis, or programmed cell death, is a mechanism that results in cells actively self-destructing without causing inflammation. Apoptosis is an essential feature in multicellular organisms, necessary during development and normal maintenance of tissues. Apoptosis can be triggered by specific signals, by cells failing to receive the required signals to avoid apoptosis, and by exposure to infectious agents such as viruses. HSCs are not exempt; apoptosis is one mechanism to regulate their numbers. This was demonstrated in transgenic mouse experiments in which HSC numbers doubled when the apoptosis threshold was increased.76 This study also showed that HSCs are particularly sensitive and require two signals to avoid undergoing apoptosis.

The best-known location for HSCs is bone marrow, and bone marrow transplantation has become synonymous with hematopoietic cell transplantation, even though bone marrow itself is increasingly infrequently used as a source due to an invasive harvesting procedure that requires general anesthesia. In adults, under steady-state conditions, the majority of HSCs reside in bone marrow. However, cytokine mobilization can result in the release of large numbers of HSCs into the blood. As a clinical source of HSCs, mobilized peripheral blood (MPB) is now replacing bone marrow, as harvesting peripheral blood is easier for the donors than harvesting bone marrow. As with bone marrow, mobilized peripheral blood contains a mixture of hematopoietic stem and progenitor cells. MPB is normally passed through a device that enriches cells that express CD34, a marker on both stem and progenitor cells. Consequently, the resulting cell preparation that is infused back into patients is not a pure HSC preparation, but a mixture of HSCs, hematopoietic progenitors (the major component), and various contaminants, including T cells and, in the case of autologous grafts from cancer patients, quite possibly tumor cells. It is important to distinguish these kinds of grafts, which are the grafts routinely given, from highly purified HSC preparations, which essentially lack other cell types.

In the late 1980s, umbilical cord blood (UCB) was recognized as an important clinical source of HSCs.100,101 Blood from the placenta and umbilical cord is a rich source of hematopoietic stem cells, and these cells are typically discarded with the afterbirth. Increasingly, UCB is harvested, frozen, and stored in cord blood banks, as an individual resource (donor-specific source) or as a general resource, directly available when needed. Cord blood has been used successfully to transplant children and (far less frequently) adults. Specific limitations of UCB include the limited number of cells that can be harvested and the delayed immune reconstitution observed following UCB transplant, which leaves patients vulnerable to infections for a longer period of time. Advantages of cord blood include its availability, ease of harvest, and the reduced risk of graft-versus-host-disease (GVHD). In addition, cord blood HSCs have been noted to have a greater proliferative capacity than adult HSCs. Several approaches have been tested to overcome the cell dose issue, including, with some success, pooling of cord blood samples.101,102 Ex vivo expansion in tissue culture, to which cord blood cells are more amenable than adult cells, is another approach under active investigation.103

The use of cord blood has opened a controversial treatment strategyembryo selection to create a related UCB donor.104 In this procedure, embryos are conceived by in vitro fertilization. The embryos are tested by pre-implantation genetic diagnosis, and embryos with transplantation antigens matching those of the affected sibling are implanted. Cord blood from the resulting newborn is then used to treat this sibling. This approach, successfully pioneered at the University of Minnesota, can in principle be applied to a wide variety of hematopoietic disorders. However, the ethical questions involved argue for clear regulatory guidelines.105

Embryonic stem (ES) cells form a potential future source of HSCs. Both mouse and human ES cells have yielded hematopoietic cells in tissue culture, and they do so relatively readily.106 However, recognizing the actual HSCs in these cultures has proven problematic, which may reflect the variability in HSC markers or the altered reconstitution behavior of these HSCs, which are expected to mimic fetal HSC. This, combined with the potential risks of including undifferentiated cells in an ES-cell-derived graft means that, based on the current science, clinical use of ES cell-derived HSCs remains only a theoretical possibility for now.

An ongoing set of investigations has led to claims that HSCs, as well as other stem cells, have the capacity to differentiate into a much wider range of tissues than previously thought possible. It has been claimed that, following reconstitution, bone marrow cells can differentiate not only into blood cells but also muscle cells (both skeletal myocytes and cardiomyocytes),107111 brain cells,112,113 liver cells,114,115 skin cells, lung cells, kidney cells, intestinal cells,116 and pancreatic cells.117 Bone marrow is a complex mixture that contains numerous cell types. In addition to HSCs, at least one other type of stem cell, the mesenchymal stem cell (MSC), is present in bone marrow. MSCs, which have become the subject of increasingly intense investigation, seem to retain a wide range of differentiation capabilities in vitro that is not restricted to mesodermal tissues, but includes tissues normally derived from other embryonic germ layers (e.g., neurons).118120MSCs are discussed in detail in Dr. Catherine Verfaillie's testimony to the President's Council on Bioethics at this website: refer to Appendix J (page 295) and will not be discussed further here. However, similar claims of differentiation into multiple diverse cell types, including muscle,111 liver,114 and different types of epithelium116 have been made in experiments that assayed partially- or fully-purified HSCs. These experiments have spawned the idea that HSCs may not be entirely or irreversibly committed to forming the blood, but under the proper circumstances, HSCs may also function in the regeneration or repair of non-blood tissues. This concept has in turn given rise to the hypothesis that the fate of stem cells is quot;plastic,quot; or changeable, allowing these cells to adopt alternate fates if needed in response to tissue-derived regenerative signals (a phenomenon sometimes referred to as quot;transdifferentiationquot;). This in turn seems to bolster the argument that the full clinical potential of stem cells can be realized by studying only adult stem cells, foregoing research into defining the conditions necessary for the clinical use of the extensive differentiation potential of embryonic stem cells. However, as discussed below, such quot;transdifferentiationquot; claims for specialized adult stem cells are controversial, and alternative explanations for these observations remain possible, and, in several cases, have been documented directly.

While a full discussion of this issue is beyond the scope of this overview, several investigators have formulated criteria that must be fulfilled to demonstrate stem cell plasticity.121,122 These include (i) clonal analysis, which requires the transfer and analysis of single, highly-purified cells or individually marked cells and the subsequent demonstration of both quot;normalquot; and quot;plasticquot; differentiation outcomes, (ii) robust levels of quot;plasticquot; differentiation outcome, as extremely rare events are difficult to analyze and may be induced by artefact, and (iii) demonstration of tissue-specific function of the quot;transdifferentiatedquot; cell type. Few of the current reports fulfill these criteria, and careful analysis of individually transplanted KTLS HSCs has failed to show significant levels of non-hematopoietic engraftment.123,124In addition, several reported trans-differentiation events that employed highly purified HSCs, and in some cases a very strong selection pressure for trans-differentiation, now have been shown to result from fusion of a blood cell with a non-blood cell, rather than from a change in fate of blood stem cells.125127 Finally, in the vast majority of cases, reported contributions of adult stem cells to cell types outside their tissue of origin are exceedingly rare, far too rare to be considered therapeutically useful. These findings have raised significant doubts about the biological importance and immediate clinical utility of adult hematopoietic stem cell plasticity. Instead, these results suggest that normal tissue regeneration relies predominantly on the function of cell type-specific stem or progenitor cells, and that the identification, isolation, and characterization of these cells may be more useful in designing novel approaches to regenerative medicine. Nonetheless, it is possible that a rigorous and concerted effort to identify, purify, and potentially expand the appropriate cell populations responsible for apparent quot;plasticityquot; events, characterize the tissue-specific and injury-related signals that recruit, stimulate, or regulate plasticity, and determine the mechanism(s) underlying cell fusion or transdifferentiation, may eventually enhance tissue regeneration via this mechanism to clinically useful levels.

Recent progress in genomic sequencing and genome-wide expression analysis at the RNA and protein levels has greatly increased our ability to study cells such as HSCs as quot;systems,quot; that is, as combinations of defined components with defined interactions. This goal has yet to be realized fully, as computational biology and system-wide protein biochemistry and proteomics still must catch up with the wealth of data currently generated at the genomic and transcriptional levels. Recent landmark events have included the sequencing of the human and mouse genomes and the development of techniques such as array-based analysis. Several research groups have combined cDNA cloning and sequencing with array-based analysis to begin to define the full transcriptional profile of HSCs from different species and developmental stages and compare these to other stem cells.64,65,128131 Many of the data are available in online databases, such as the NIH/NIDDK Stem Cell Genome Anatomy Projects. While transcriptional profiling is clearly a work in progress, comparisons among various types of stem cells may eventually identify sets of genes that are involved in defining the general quot;stemnessquot; of a cell, as well as sets of genes that define their exit from the stem cell pool (e.g., the beginning of their path toward becoming mature differentiated cells, also referred to as commitment). In addition, these datasets will reveal sets of genes that are associated with specific stem cell populations, such as HSCs and MSCs, and thus define their unique properties. Assembly of these datasets into pathways will greatly help to understand and to predict the responses of HSCs (and other stem cells) to various stimuli.

The clinical use of stem cells holds great promise, although the application of most classes of adult stem cells is either currently untested or is in the earliest phases of clinical testing.132,133 The only exception is HSCs, which have been used clinically since 1959 and are used increasingly routinely for transplantations, albeit almost exclusively in a non-pure form. By 1995, more than 40,000 transplants were performed annually world-wide.134,135 Currently the main indications for bone marrow transplantation are either hematopoietic cancers (leukemias and lymphomas), or the use of high-dose chemotherapy for non-hematopoietic malignancies (cancers in other organs). Other indications include diseases that involve genetic or acquired bone marrow failure, such as aplastic anemia, thalassemia sickle cell anemia, and increasingly, autoimmune diseases.

Transplantation of bone marrow and HSCs are carried out in two rather different settings, autologous and allogeneic. Autologous transplantations employ a patient's own bone marrow tissue and thus present no tissue incompatibility between the donor and the host. Allogeneic transplantations occur between two individuals who are not genetically identical (with the rare exceptions of transplantations between identical twins, often referred to as syngeneic transplantations). Non-identical individuals differ in their human leukocyte antigens (HLAs), proteins that are expressed by their white blood cells. The immune system uses these HLAs to distinguish between quot;selfquot; and quot;nonself.quot; For successful transplantation, allogeneic grafts must match most, if not all, of the six to ten major HLA antigens between host and donor. Even if they do, however, enough differences remain in mostly uncharacterized minor antigens to enable immune cells from the donor and the host to recognize the other as quot;nonself.quot; This is an important issue, as virtually all HSC transplants are carried out with either non-purified, mixed cell populations (mobilized peripheral blood, cord blood, or bone marrow) or cell populations that have been enriched for HSCs (e.g., by column selection for CD34+ cells) but have not been fully purified. These mixed population grafts contain sufficient lymphoid cells to mount an immune response against host cells if they are recognized as quot;non-self.quot; The clinical syndrome that results from this quot;non-selfquot; response is known as graft-versus-host disease (GVHD).136

In contrast, autologous grafts use cells harvested from the patient and offer the advantage of not causing GVHD. The main disadvantage of an autologous graft in the treatment of cancer is the absence of a graft-versusleukemia (GVL) or graft-versus-tumor (GVT) response, the specific immunological recognition of host tumor cells by donor-immune effector cells present in the transplant. Moreover, the possibility exists for contamination with cancerous or pre-cancerous cells.

Allogeneic grafts also have disadvantages. They are limited by the availability of immunologically-matched donors and the possibility of developing potentially lethal GVHD. The main advantage of allogeneic grafts is the potential for a GVL response, which can be an important contribution to achieving and maintaining complete remission.137,138

Today, most grafts used in the treatment of patients consist of either whole or CD34+-enriched bone marrow or, more likely, mobilized peripheral blood. The use of highly purified hematopoietic stem cells as grafts is rare.5658 However, the latter have the advantage of containing no detectable contaminating tumor cells in the case of autologous grafts, therefore not inducing GVHD, or presumably GVL,139141in allogeneic grafts. While they do so less efficiently than lymphocyte-containing cell mixtures, HSCs alone can engraft across full allogeneic barriers (i.e., when transplanted from a donor who is a complete mismatch for both major and minor transplantation antigens).139141The use of donor lymphocyte infusions (DLI) in the context of HSC transplantation allows for the controlled addition of lymphocytes, if necessary, to obtain or maintain high levels of donor cells and/or to induce a potentially curative GVL-response.142,143 The main problems associated with clinical use of highly purified HSCs are the additional labor and costs144 involved in obtaining highly purified cells in sufficient quantities.

While the possibilities of GVL and other immune responses to malignancies remain the focus of intense interest, it is also clear that in many cases, less-directed approaches such as chemotherapy or irradiation offer promise. However, while high-dose chemotherapy combined with autologous bone marrow transplantation has been reported to improve outcome (usually measured as the increase in time to progression, or increase in survival time),145154 this has not been observed by other researchers and remains controversial.155161 The tumor cells present in autologous grafts may be an important limitation in achieving long-term disease-free survival. Only further purification/ purging of the grafts, with rigorous separation of HSCs from cancer cells, can overcome this limitation. Initial small scale trials with HSCs purified by flow cytometry suggest that this is both possible and beneficial to the clinical outcome.56 In summary, purification of HSCs from cancer/lymphoma/leukemia patients offers the only possibility of using these cells post-chemotherapy to regenerate the host with cancer-free grafts. Purification of HSCs in allotransplantation allows transplantation with cells that regenerate the blood-forming system but cannot induce GVHD.

An important recent advance in the clinical use of HSCs is the development of non-myeloablative preconditioning regimens, sometimes referred to as quot;mini transplants.quot;162164 Traditionally, bone marrow or stem cell transplantation has been preceded by a preconditioning regimen consisting of chemotherapeutic agents, often combined with irradiation, that completely destroys host blood and bone marrow tissues (a process called myeloablation). This creates quot;spacequot; for the incoming cells by freeing stem cell niches and prevents an undesired immune response of the host cells against the graft cells, which could result in graft failure. However, myeloablation immunocompromises the patient severely and necessitates a prolonged hospital stay under sterile conditions. Many protocols have been developed that use a more limited and targeted approach to preconditioning. These nonmyeloablative preconditioning protocols, which combine excellent engraftment results with the ability to perform hematopoietic cell transplantation on an outpatient basis, have greatly changed the clinical practice of bone marrow transplantation.

FACS purification of HSCs in mouse and man completely eliminates contaminating T cells, and thus GVHD (which is caused by T-lymphocytes) in allogeneic transplants. Many HSC transplants have been carried out in different combinations of mouse strains. Some of these were matched at the major transplantation antigens but otherwise different (Matched Unrelated Donors or MUD); in others, no match at the major or minor transplantation antigens was expected. To achieve rapid and sustained engraftment, higher doses of HSCs were required in these mismatched allogeneic transplants than in syngeneic transplants.139141,165167 In these experiments, hosts whose immune and blood-forming systems were generated from genetically distinct donors were permanently capable of accepting organ transplants (such as the heart) from either donor or host, but not from mice unrelated to the donor or host. This phenomenon is known as transplant-induced tolerance and was observed whether the organ transplants were given the same day as the HSCs or up to one year later.139,166Hematopoietic cell transplant-related complications have limited the clinical application of such tolerance induction for solid organ grafts, but the use of non-myeloablative regimens to prepare the host, as discussed above, should significantly reduce the risk associated with combined HSC and organ transplants. Translation of these findings to human patients should enable a switch from chronic immunosuppression to prevent rejection to protocols wherein a single conditioning dose allows permanent engraftment of both the transplanted blood system and solid organ(s) or other tissue stem cells from the same donor. This should eliminate both GVHD and chronic host transplant immunosuppression, which lead to many complications, including life-threatening opportunistic infections and the development of malignant neoplasms.

We now know that several autoimmune diseasesdiseases in which immune cells attack normal body tissuesinvolve the inheritance of high risk-factor genes.168 Many of these genes are expressed only in blood cells. Researchers have recently tested whether HSCs could be used in mice with autoimmune disease (e.g., type 1 diabetes) to replace an autoimmune blood system with one that lacks the autoimmune risk genes. The HSC transplants cured mice that were in the process of disease development when nonmyeloablative conditioning was used for transplant.169 It has been observed that transplant-induced tolerance allows co-transplantation of pancreatic islet cells to replace destroyed islets.170 If these results using nonmyeloablative conditioning can be translated to humans, type 1 diabetes and several other autoimmune diseases may be treatable with pure HSC grafts. However, the reader should be cautioned that the translation of treatments from mice to humans is often complicated and time-consuming.

Banking is currently a routine procedure for UCB samples. If expansion of fully functional HSCs in tissue culture becomes a reality, HSC transplants may be possible by starting with small collections of HSCs rather than massive numbers acquired through mobilization and apheresis. With such a capability, collections of HSCs from volunteer donors or umbilical cords could be theoretically converted into storable, expandable stem cell banks useful on demand for clinical transplantation and/or for protection against radiation accidents. In mice, successful HSC transplants that regenerate fully normal immune and blood-forming systems can be accomplished when there is only a partial transplantation antigen match. Thus, the establishment of useful human HSC banks may require a match between as few as three out of six transplantation antigens (HLA). This might be accomplished with stem cell banks of as few as 4,00010,000 independent samples.

Leukemias are proliferative diseases of the hematopoietic system that fail to obey normal regulatory signals. They derive from stem cells or progenitors of the hematopoietic system and almost certainly include several stages of progression. During this progression, genetic and/or epigenetic changes occur, either in the DNA sequence itself (genetic) or other heritable modifications that affect the genome (epigenetic). These (epi)genetic changes alter cells from the normal hematopoietic system into cells capable of robust leukemic growth. There are a variety of leukemias, usually classified by the predominant pathologic cell types and/or the clinical course of the disease. It has been proposed that these are diseases in which self-renewing but poorly regulated cells, so-called "leukemia stem cells" (LSCs), are the populations that harbor all the genetic and epigenetic changes that allow leukemic progression.171176 While their progeny may be the characteristic cells observed with the leukemia, these progeny cells are not the self-renewing "malignant" cells of the disease. In this view, the events contributing to tumorigenic transformation, such as interrupted or decreased expression of "tumor suppressor" genes, loss of programmed death pathways, evasion of immune cells and macrophage surveillance mechanisms, retention of telomeres, and activation or amplification of self-renewal pathways, occur as single, rare events in the clonal progression to blast-crisis leukemia. As LT HSCs are the only selfrenewing cells in the myeloid pathway, it has been proposed that most, if not all, progression events occur at this level of differentiation, creating clonal cohorts of HSCs with increasing malignancy (see Figure 2.6). In this disease model, the final event, explosive selfrenewal, could occur at the level of HSC or at any of the known progenitors (see Figures 2.5 and 2.6). Activation of the -catenin/lef-tcf signal transduction and transcription pathway has been implicated in leukemic stem cell self-renewal in mouse AML and human CML.177 In both cases, the granulocyte-macrophage progenitors, not the HSCs or progeny blast cells, are the malignant self-renewing entities. In other models, such as the JunB-deficient tumors in mice and in chronic-phase CML in humans, the leukemic stem cell is the HSC itself.90,177 However, these HSCs still respond to regulatory signals, thus representing steps in the clonal progression toward blast crisis (see Figure 2.6).

Figure 2.6. Leukemic progression at the hematopoietic stem cell level. Self-renewing HSCs are the cells present long enough to accumulate the many activating events necessary for full transformation into tumorigenic cells. Under normal conditions, half of the offspring of HSC cell divisions would be expected to undergo differentiation, leaving the HSC pool stable in size. (A) (Pre) leukemic progression results in cohorts of HSCs with increasing malignant potential. The cells with the additional event (two events are illustrated, although more would be expected to occur) can outcompete less-transformed cells in the HSC pool if they divide faster (as suggested in the figure) or are more resistant to differentiation or apoptosis (cell death), two major exit routes from the HSC pool. (B) Normal HSCs differentiate into progenitors and mature cells; this is linked with limited proliferation (left). Partially transformed HSCs can still differentiate into progenitors and mature cells, but more cells are produced. Also, the types of mature cells that are produced may be skewed from the normal ratio. Fully transformed cells may be completely blocked in terminal differentiation, and large numbers of primitive blast cells, representing either HSCs or self-renewing, transformed progenitor cells, can be produced. While this sequence of events is true for some leukemias (e.g., AML), not all of the events occur in every leukemia. As with non-transformed cells, most leukemia cells (other than the leukemia stem cells) can retain the potential for (limited) differentiation.

Many methods have revealed contributing protooncogenes and lost tumor suppressors in myeloid leukemias. Now that LSCs can be isolated, researchers should eventually be able to assess the full sequence of events in HSC clones undergoing leukemic transformation. For example, early events, such as the AML/ETO translocation in AML or the BCR/ABL translocation in CML can remain present in normal HSCs in patients who are in remission (e.g., without detectable cancer).177,178 The isolation of LSCs should enable a much more focused attack on these cells, drawing on their known gene expression patterns, the mutant genes they possess, and the proteomic analysis of the pathways altered by the proto-oncogenic events.173,176,179 Thus, immune therapies for leukemia would become more realistic, and approaches to classify and isolate LSCs in blood could be applied to search for cancer stem cells in other tissues.180

After more than 50 years of research and clinical use, hematopoietic stem cells have become the best-studied stem cells and, more importantly, hematopoietic stem cells have seen widespread clinical use. Yet the study of HSCs remains active and continues to advance very rapidly. Fueled by new basic research and clinical discoveries, HSCs hold promise for such indications as treating autoimmunity, generating tolerance for solid organ transplants, and directing cancer therapy. However, many challenges remain. The availability of (matched) HSCs for all of the potential applications continues to be a major hurdle. Efficient expansion of HSCs in culture remains one of the major research goals. Future developments in genomics and proteomics, as well as in gene therapy, have the potential to widen the horizon for clinical application of hematopoietic stem cells even further.

Notes:

* Cellerant Therapeutics, 1531 Industrial Road, San Carlos, CA 94070. Current address: Department of Surgery, Arizona Health Sciences Center, 1501 N. Campbell Avenue, P.O. Box 245071, Tucson, AZ 857245071,e-mail: jdomen@surgery.arizona.edu.

** Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, E-mail: Amy_Wagers@harvard.edu

*** Director, Institute for Cancer/Stem Cell Biology and Medicine, Professor of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, Irv@stanford.edu.

Chapter1|Table of Contents|Chapter3

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Bone Marrow (Hematopoietic) Stem Cells | stemcells.nih.gov

Deep imaging of bone marrow shows non-dividing stem cells …

a, Hindlimb bone marrow cellularity (n=9 mice for -catulin+/+,n=4 mice for -catulinGFP/+ and n=9 mice for -catulinGFP/GFP genotype) and spleen cellularity (n=6 mice for -catulin+/+,n=4 mice for -catulinGFP/+ and n=6 mice for -catulinGFP/GFP genotype), spleen mass (7 mice for -catulin+/+,n=4 mice for -catulinGFP/+ and n=7 mice for -catulinGFP/GFP genotype). b, White blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts per microliter of peripheral blood from 812 week old -catulin+/+, -catulinGFP/+, and -catulinGFP/GFP mice (n=9 mice/genotype). c,d, Frequencies of mature hematopoietic cells and progenitors in the bone marrow of 812 week old -catulin+/+ and -catulinGFP/GFP mice (Pre-ProB cells were B220+sIgMCD43+CD24; ProB cells were B220+sIgMCD43+CD24+; Pre-B cells were B220+sIgMCD43; common lymphoid progenitors (CLPs) were Linc-kitlowSca1lowCD127+CD135+; common myeloid progenitors (CMPs) were Linc-kit+Sca1CD34+CD16/32; granulocyte-macrophage progenitors (GMPs) were Linc-kit+Sca1CD34+CD16/32+; and megakaryocyte-erythroid progenitors (MEPs) were Linc-kit+Sca1CD34CD16/32 (n=3 mice/genotype). e, Bone marrow CD150+CD48LSK HSC frequency, bone marrow CD150CD48LSK MPP frequency (n=12 mice/genotype in 12 independent experiments), and spleen HSC frequency (n=3 mice/genotype in 3 experiments). f, Percentage of HSCs and whole bone marrow cells that incorporated a 3 day pulse of BrdU in vivo (n=6 -catulin+/+, 9 -catulinGFP/+, and 7 -catulinGFP/GFP 812 week old mice in 3 independent experiments). g, Colony formation by HSCs in methylcellulose cultures (GM means granulocyte-macrophage colonies, GEMM means granulocyte-erythroid-macrophage-megakaryocyte colonies, Mk means megakaryocyte colonies; (n=5 mice/genotype in 5 independent experiments). h, Reconstitution of irradiated mice by 300,000 donor bone marrow cells from 812 week old -catulin+/+, -catulinGFP/+, or -catulinGFP/GFP mice competed against 300,000 recipient bone marrow cells (n=4 donor mice and 16 recipient mice for -catulin+/+, n=3 donor mice and 9 recipient mice for -catulinGFP/+, and n=4 donor mice and 18 recipients for -catulinGFP/GFP in 3 independent experiments). i, Serial transplantation of 3 million WBM cells from primary recipient mice shown in panel d into irradiated secondary recipient mice (n=4 primary -catulin+/+ recipients were transplanted into 17 secondary recipients and n=6 primary -catulinGFP/GFP recipients were transplanted into 20 secondary recipients). All data represent means.d. The statistical significance of differences between genotypes was assessed using Students t-tests or ANOVAs. None were significant.

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Deep imaging of bone marrow shows non-dividing stem cells ...

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Human peripheral blood cells are isolated from adult whole blood or from a leukapheresis preparation produced using state-of-the-art apheresis systems. These apheresis collections, known as "Leuko Paks", contain very high concentrations of mononuclear cells and are available in the following Pak sizes: full, half and quarter Pak. Specific cell subsets are purified using STEMCELL's cell isolation products. Fresh whole blood products are collected directly into blood bags using acid-citrate-dextrose solution A (ACDA) or citrate-phosphate-dextrose (CPD) as the anticoagulant.

Human cord blood is collected using citrate-phosphate-dextrose (CPD) as the anticoagulant. Mononuclear cells are obtained by density gradient centrifugation. Specific cell subsets are obtained using STEMCELLs cell isolation products.

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Cryopreserved Leuko Pak and Whole Blood Products

Donor Screening: Donors are screened for HIV (1 & 2), Hepatitis B, and Hepatitis C. Cryopreserved products are shipped with negative test results from donor screening that is done within 90 days of collection.

Fresh Leuko Pak and Whole Blood Products

Donor Screening: Donors are screened for HIV (1 & 2), Hepatitis B, and Hepatitis C. If the donor was screened within 90 days of donation the product will be shipped with negative test results from donor screening. If the donor was not screened within 90 days of collection, a test sample will be taken at the time of donation and the product will be shipped before the screening results are available. In the unlikely event that a test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

Cryopreserved Cord Blood Products

Donor Screening: Cord blood is only collected from mothers that have tested negative for HIV (1 & 2) and Hepatitis B during their pregnancy. Hepatitis C is tested for at the time of collection. Cryopreserved products are shipped with negative test results from donor screening.

Fresh Cord Blood Products

Donor Screening: Cord blood is only collected from mothers that have tested negative for HIV (1 & 2) and Hepatitis B during their pregnancy. Hepatitis C is tested for at the time of collection. Fresh cord blood products are shipped with negative test results for HIV (1 & 2) and Hepatitis B donor screening. Hepatitis C test results are not available at the time of shipment. In the unlikely event that the Hepatitis C test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

Shipment date of fresh Leuko Pak or whole blood orders is subject to change based on the ability of donors to meet procedural requirements during collection or on changes in donor availability. Collections will be rescheduled as soon as possible according to customer requirements.

STEMCELL does not test for infectious diseases other than those listed above and the testing that is done cannot completely guarantee that the donor was virus-free. Therefore THESE PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS and only used following appropriate handling precautions such as those described in biological safety level 2. When handling these products do not use sharps such as needles and syringes.

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Primary Cells Overview - stemcell.com

Peripheral-blood stem cells versus bone marrow from …

See comment in PubMed Commons below N Engl J Med. 2012 Oct 18;367(16):1487-96. doi: 10.1056/NEJMoa1203517. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Collaborators (182)

Horowitz MM, Carter SL, Confer DL, DiFronzo N, Wagner E, Merritt W, Wu R, Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Couban S, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Carter SL, Karanes C, Horowitz MM, Confer DL, Allen C, Colby C, Gurgol C, Knust K, Foley A, King R, Mitchell P, Couban S, Pulsipher MA, Ehninger G, Johnston L, Khan SP, Maziarz RT, McCarty JM, Mineishi S, Porter DL, Bredeson C, Anasetti C, Lee S, Waller EK, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Logan BR, Carter SL, Lee SJ, Waller EK, Anasetti C, Logan BR, Lee SJ, Stadtmauer E, Wingard J, Vose J, Lazarus H, Cowan M, Wingard J, Westervelt P, Litzow M, Wu R, Geller N, Carter S, Confer D, Horowitz M, Poland N, Krance R, Carrum G, Agura E, Nademanee A, Sahdev I, Cutler C, Horwitz ME, Kurtzberg J, Waller EK, Woolfrey A, Rowley S, Brochstein J, Leber B, Wasi P, Roy J, Jansen J, Stiff PJ, Khan S, Devine S, Maziarz R, Nemecek E, Huebsch L, Couban S, McCarthy P, Johnston L, Shaughnessy P, Savoie L, Ball E, Vaughan W, Cowan M, Horn B, Wingard J, Silverman M, Abhyankar S, McGuirk J, Yanovich S, Ferrara J, Weisdorf D, Faber E Jr, Selby G, Rooms LM, Porter D, Agha M, Anderlini P, Lipton J, Pulsipher MA, Pulsipher MA, Shepherd J, Toze C, Kassim A, Frangoul H, McCarty J, Hurd D, DiPersio J, Westervelt P, Shenoy S, Agura E, Culler E, Axelrod F, Chambers L, Senaldi E, Nguyen KA, Engelman E, Hartzman R, Sutor L, Dickson L, Nademanee A, Khalife G, Lenes BA, Eames G, Sibley D, Gale P, Antin J, Ehninger G, Newberg NR, Gammon R, Montgomery M, Mair B, Rossmann S, Wada R, Waxman D, Ranlett R, Silverman M, Herzig G, Fried M, Atkinson E, Weitekamp L, Bigelow C, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Price T, Young C, Hilbert R, Oh D, Cable C, Smith JW, Kalmin ND, Schultheiss K, Beck T, Lankiewicz MW, Sharp D.

Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.

We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).

The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.

We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Survival after Randomization in the Intention-to-Treat Analysis

The P value is from a stratified binomial comparison at the 2-year point. The P value from a stratified log-rank test was also not significant. A total of 75 patients in each group were still alive at 36 months.

N Engl J Med. ;367(16):10.1056/NEJMoa1203517.

Outcomes after Transplantation, According to Study Group

Panel A shows the rate of overall survival, and Panel B the rate of disease-free survival. Panel C shows the incidence of death unrelated to relapse. Panel D shows the incidence of relapse. Panel E shows the incidence of neutrophil engraftment (>500 neutrophils per cubic millimeter), and Panel F the incidence of platelet engraftment (>20,000 platelets per cubic millimeter, without platelet transfusion during the prior 7 days). Panel G shows the incidence of acute graft-versus-host disease (GVHD) of grades II to IV, and Panel H the incidence of chronic GVHD. P values for the between-group differences in overall survival (Panel A) and disease-free survival (Panel B) are from a stratified binomial comparison at the 2-year point; P values from stratified log-rank tests for survival and disease-free survival were also not significant. All other P values shown are from stratified log-rank tests.

N Engl J Med. ;367(16):10.1056/NEJMoa1203517.

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Peripheral-blood stem cells versus bone marrow from ...

Comparative Analysis of Mesenchymal Stem Cells from Bone …

Abstract

Mesenchymal stem cells (MSCs) represent a promising tool for new clinical concepts in supporting cellular therapy. Bone marrow (BM) was the first source reported to contain MSCs. However, for clinical use, BM may be detrimental due to the highly invasive donation procedure and the decline in MSC number and differentiation potential with increasing age. More recently, umbilical cord blood (UCB), attainable by a less invasive method, was introduced as an alternative source for MSCs. Another promising source is adipose tissue (AT). We compared MSCs derived from these sources regarding morphology, the success rate of isolating MSCs, colony frequency, expansion potential, multiple differentiation capacity, and immune phenotype. No significant differences concerning the morphology and immune phenotype of the MSCs derived from these sources were obvious. Differences could be observed concerning the success rate of isolating MSCs, which was 100% for BM and AT, but only 63% for UCB. The colony frequency was lowest in UCB, whereas it was highest in AT. However, UCB-MSCs could be cultured longest and showed the highest proliferation capacity, whereas BM-MSCs possessed the shortest culture period and the lowest proliferation capacity. Most strikingly, UCB-MSCs showed no adipogenic differentiation capacity, in contrast to BM- and AT-MSCs. Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.

Mesenchymal stem cells (MSCs) found in many adult tissues are an attractive stem cell source for the regeneration of damaged tissues in clinical applications because they are characterized as undifferentiated cells, able to self-renew with a high proliferative capacity, and possess a mesodermal differentiation potential [1].

Although bone marrow (BM) has been the main source for the isolation of multipotent MSCs, the harvest of BM is a highly invasive procedure and the number, differentiation potential, and maximal life span of MSCs from BM decline with increasing age [24]. Therefore, alternative sources from which to isolate MSCs are subject to intensive investigation.

One alternative source is umbilical cord blood (UCB), which can be obtained by a less invasive method, without harm for the mother or the infant [5]. However, controversy still exists whether full-term UCB can serve as a source for isolating multipotent MSCs: although some groups did not succeed in isolating MSCs [6, 7], we and other groups succeeded in isolating MSCs from full-term UCB [812].

Adipose tissue (AT) is another alternative source that can be obtained by a less invasive method and in larger quantities than BM. It has been demonstrated that AT contains stem cells similar to BM-MSCs, which are termed processed lipoaspirate (PLA) cells [13]. These cells can be isolated from cosmetic liposuctions in large numbers and grown easily under standard tissue culture conditions [13]. The multilineage differentiation capacity of PLA cells has been confirmed [13].

As BM-MSCs are best characterized, we asked whether MSCs derived from other sources share the characteristics of BM-MSCs. The aim of our study was to compare MSCs isolated from the three sources under identical in vitro conditions with respect to their morphology, frequency of colonies, expansion characteristics, multilineage differentiation capacity, immunophenotype, and success rate of isolating the cells.

We compared MSCs from BM and two alternative sources, namely UCB and AT, concerning basic MSC characteristics. All cells isolated from these three sources exhibited typical MSC characteristics: a fibroblastoid morphology, the formation of CFU-F, a multipotential differentiation capability, and the expression of a typical set of surface proteins. Whereas MSCs derived from the three sources expressed classic MSC marker proteins, but lacked hematopoietic and endothelial markers, we observed significant differences concerning the expression of CD90, CD105, and CD106. These molecules are described to be associated with hematopoiesis and cell migration [18 20]. It needs to be further investigated whether these molecules are functionally important for stroma and homing capacities. In a first approach, we created a comprehensive protein expression profile of undifferentiated UCB-MSCs, which will be extended to BM- and AT-MSCs and then correlated to functional properties [21].

Since the relevance of the observed differences of marker expression has not been properly investigated yet, differences concerning differentiation capacity seem to be more relevant for MSC quality at present. We demonstrated a multilineage differentiation capacity for BM- and AT-MSCs. Interestingly, UCB-MSCs could not be differentiated toward the adipogenic lineage, which was not related to the CFU-F origin. Actually, there are conflicting data concerning the adipogenic differentiation capacity of UCB-MSCs [9 12, 22, 23]. Nevertheless, we assume that UCB-MSCs are less sensitive toward the adipogenic differentiation (supported by results of Chang et al. [22]) which might be related to the ontogenetic age of these cells. This is further supported by the fact that adipocytes reside in adult human BM and AT but are absent in fetal BM and by the observation of an increased adipogenesis correlated with age [24]. Further comparative genomic or proteomic approaches are needed to assess the susceptibility toward adipogenesis of MSCs.

None of our UCB-MSCs showed adipogenic differentiation capacity, but all differentiated into both the chondro- and osteogenic lineages. In contrast, a tripotential differentiation capacity was observed for most AT samples but only for a few BM samples. One sample each of BM and AT was observed to undergo only the chondrogenic pathway. In accordance with this, a hierarchical or even restricted differentiation potential of MSCs has been reported [1, 13, 25].

In our study, investigations were limited to the mesodermal differentiation capacity. Based on recent reports, however, the spectrum of differentiation of MSCs does not seem to be restricted to this lineage. MSCs derived from all three tissues have been shown to differentiate into further mesodermal lineages and into endo- and ectodermal lineages as well [10 13, 26 33]. Comparative experiments need to be performed to assess responsiveness toward cardiomyogenic, endothelial, hepatic, neuronal, and pancreatic differentiation.

A high impact on clinical exploitation might be related to the abundance and expansion capacity of MSCs. Based on our results, both BM and AT are reliable sources for isolating and expanding MSCs in autologous settings since all preparations gave rise to MSCs. UCB, in contrast, had an isolation efficacy of a maximum of 63% [8]. We attribute these differences to the fact that MSCs are circulating in the prenatal organism and are residing in tissues of the adult [9]. Despite the low frequency of UCB-MSCs, the expansion potential was highest compared with other cell sources. Considering clinical applications, the resulting cell numbers may be similar to both BM and AT, which can be obtained at higher frequencies. One argument against AT might be the limited availability in some patients. However, we believe that due to the high frequency of AT-MSCs, also small fat reservoirs might be sufficient for MSC isolation. BM has been the main source for clinical application of MSCs, such as the treatment of osteogenesis imperfecta, graft versus host disease, and acute myocardial infarction [3436]. As the number, frequency, and differentiation capacity of BM-MSCs correlate negatively with age, they could be clinically inefficient when derived from elderly patients. In that case, an allogeneic approach would be required. In case a matching donor is required, BM or AT from HLA identical siblings, haplo-identical relatives, or HLA-screened donors might be best choice. Speculating on a off-the-shelf product requiring mass production, AT might be a solid starting basis due to the abundance, relatively easy harvest, and high MSCs frequency.

Transplantation of MSCs is currently a highly experimental procedure, resembling the early beginnings of hematopoietic stem cell transplantation. In the latter, BM has been replaced gradually by peripheral blood progenitor cells and umbilical cord blood. Also, in the field of MSCs, alternative sources are intensely investigated, and one day these new sources may replace BM. Taking into account all the advantages and disadvantages of the three sources discussed above, depending on the therapeutic indication, the clinical applications may be based on differentiation capacity, but more likely on the abundance, frequency, and expansion potential of the cells.

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Comparative Analysis of Mesenchymal Stem Cells from Bone ...

What is a Stem Cell Transplant (Bone Marrow Transplant …

A stem cell transplant is a treatment for some types of cancer. For example, you might have one if you have leukemia, multiple myeloma, or some types of lymphoma. Doctors also treat some blood diseases with stem cell transplants.

In the past, patients who needed a stem cell transplant received a bone marrow transplant because the stem cells were collected from the bone marrow. Today, stem cells are usually collected from the blood, instead of the bone marrow. For this reason, they are now more commonly called stem cell transplants.

A part of your bones called bone marrow makes blood cells. Marrow is the soft, spongy tissue inside bones. It contains cells called hematopoietic stem cells (pronounced he-mah-tuh-poy-ET-ick). These cells can turn into several other types of cells. They can turn into more bone marrow cells. Or they can turn into any type of blood cell.

Certain cancers and other diseases keep hematopoietic stem cells from developing normally. If they are not normal, neither are the blood cells that they make. A stem cell transplant gives you new stem cells. The new stem cells can make new, healthy blood cells.

The main types of stem cell transplants and other options are discussed below.

Autologous transplant. Doctors call this an AUTO transplant. This type of stem cell transplant may also be called high-dose chemotherapy with autologous stem cell rescue.

In an AUTO transplant, you get your own stem cells after doctors treat the cancer. First, your health care team collects stem cells from your blood and freezes them. Next, you have powerful chemotherapy, and rarely, radiation therapy. Then, your health care team thaws your frozen stem cells. They put them back in your blood through a tube placed in a vein (IV).

It takes about 24 hours for your stem cells to reach the bone marrow. Then they start to grow, multiply, and help the marrow make healthy blood cells again.

Allogeneic transplantation. Doctors call this an ALLO transplant.

In an ALLO transplant, you get another persons stem cells. It is important to find someone whose bone marrow matches yours. This is because you have certain proteins on your white blood cells called human leukocyte antigens (HLA). The best donor has HLA proteins as much like yours as possible.

Matching proteins make a serious condition called graft-versus-host disease (GVHD) less likely. In GVHD, healthy cells from the transplant attack your cells. A brother or sister may be the best match. But another family member or volunteer might work.

Once you find a donor, you receive chemotherapy with or without radiation therapy. Next, you get the other persons stem cells through a tube placed in a vein (IV). The cells in an ALLO transplant are not typically frozen. So, doctors can give you the cells as soon after chemotherapy or radiation therapy as possible.

There are 2 types of ALLO transplants. The best type for each patient depends his or her age and health and the type of disease being treated.

Ablative, which uses high-dose chemotherapy

Reduced intensity, which uses milder doses of chemotherapy

If your health care team cannot find a matched adult donor, there are other options. Research is ongoing to determine which type of transplant will work best for different patients.

Umbilical cord blood transplant. This may be an option if you cannot find a donor match. Cancer centers around the world use cord blood.

Parent-child transplant and haplotype mismatched transplant. These types of transplants are being used more commonly. The match is 50%, instead of near 100%. Your donor might be a parent, child, brother, or sister.

Your doctor will recommend an AUTO or ALLO transplant based mostly on the disease you have. Other factors include the health of your bone marrow and your age and general health. For example, if you have cancer or other disease in your bone marrow, you will probably have an ALLO transplant. In this situation, doctors do not recommend using your own stem cells.

Choosing a transplant is complicated. You will need help from a doctor who specializes in transplants. So you might need to travel to a center that does many stem cell transplants. Your donor might need to go, too. At the center, you talk with a transplant specialist and have an examination and tests. Before a transplant, you should also think about non-medical factors. These include:

Who can care for you during treatment

How long you will be away from work and family responsibilities

If your insurance pays for the transplant

Who can take you to transplant appointments

Your health care team can help you find answers to these questions.

The information below tells you the main parts of AUTO and ALLO transplants. Your health care team usually does the steps in order. But sometimes certain steps happen in advance, such as collecting stem cells. Ask your doctor what to expect before, during, and after a transplant.

A doctor puts a thin tube called a transplant catheter in a large vein. The tube stays in until after the transplant. Your health care team will collect stem cells through this tube and give chemotherapy and other medications through the tube.

You get injections of a medication to raise your number of white blood cells. White blood cells help your body fight infections.

Your health care team collects stem cells, usually from your blood.

Time: 1 to 2 weeks

Where its done: Clinic or hospital building. You do not need to stay in the hospital overnight.

Time: 5 to 10 days

Where its done: Clinic or hospital. At many transplant centers, patients need to stay in the hospital for the duration of the transplant, usually about 3 weeks. At some centers, patients receive treatment in the clinic and can come in every day.

Time: Each infusion usually takes less than 30 minutes. You may receive more than 1 infusion.

Where its done: Clinic or hospital.

Time: approximately 2 weeks

Where its done: Clinic or hospital. You might be staying in the hospital or you might not.

Time: Varies based on how the stem cells are collected

Where its done: Clinic or hospital

Time: 5 to 7 days

Where its done: Many ALLO transplants are done in the hospital.

Time: 1 day

Where its done: Clinic or hospital.

You take antibiotics and other drugs. This includes medications to prevent graft-versus-host disease. You get blood transfusions through your catheter if needed. Your health care team takes care of any side effects from the transplant.

After the transplant, patients visit the clinic frequently at first and less often over time.

Time: Varies

For an ablative transplant, patients are usually in the hospital for about 4 weeks in total.

For a reduced intensity transplant, patients are in the hospital or visit the clinic daily for about 1 week.

The words successful transplant might mean different things to you, your family, and your doctor. Below are 2 ways to measure transplant success.

Your blood counts are back to safe levels. A blood count is the number of red cells, white cells, and platelets in your blood. A transplant makes these numbers very low for 1 to 2 weeks. This causes risks of:

Infection from low numbers of white cells, which fight infections

Bleeding from low numbers of platelets, which stop bleeding

Tiredness from low numbers of red cells, which carry oxygen

Doctors lower these risks by giving blood and platelet transfusions after a transplant. You also take antibiotics to help prevent infections. When the new stem cells multiply, they make more blood cells. Then your blood counts improve. This is one way to know if a transplant is a success.

It controls your cancer. Doctors do stem cell transplants with the goal of curing disease. A cure may be possible for some cancers, such as some types of leukemia and lymphoma. For other patients, remission is the best result. Remission is having no signs or symptoms of cancer. After a transplant, you need to see your doctor and have tests to watch for any signs of cancer or complications from the transplant.

Talking often with the doctor is important. It gives you information to make health care decisions. The questions below may help you learn more about stem cell transplant. You can also ask other questions that are important to you.

Which type of stem cell transplant would you recommend? Why?

If I will have an ALLO transplant, how will we find a donor? What is the chance of a good match?

What type of treatment will I have before the transplant? Will radiation therapy be used?

How long will my treatment take? How long will I stay in the hospital?

How will a transplant affect my life? Can I work? Can I exercise and do regular activities?

How will we know if the transplant works?

What if the transplant doesnt work? What if the cancer comes back?

What are the side effects? This includes short-term, such as during treatment and shortly after. It also includes long-term, such as years later.

What tests will I need later? How often will I need them?

If I am worried about managing the costs of treatment, who can help me with these concerns?

Bone Marrow Aspiration and Biopsy

Making Decisions About Cancer Treatment

Donating Blood and Platelets

Donating Umbilical Cord Blood

Explore BMT

Be the Match: National Marrow Donor Program

Blood & Marrow Transplant Information Network

U.S. Department of Health and Human Services: Understanding Transplantation as a Treatment Option

National Bone Marrow Transplant Link

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What is a Stem Cell Transplant (Bone Marrow Transplant ...

Bone marrow mesenchymal stem cells: biological properties …

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are present in practically all tissues as a specialized population of mural cells/pericytes that lie on the abluminal side of blood vessels. Originally identified within the bone marrow (BM) stroma, not only do they provide microenvironmental support for hematopoietic stem cells (HSCs), but can also differentiate into various mesodermal lineages. MSCs can easily be isolated from the BM and subsequently expand in vitro and in addition they exhibit intriguing immunomodulatory properties, thereby emerging as attractive candidates for various therapeutic applications. This review addresses the concept of BM MSCs via a hematologist's point of view. In this context it discusses the stem cell properties that have been attributed to BM MSCs, as compared to those of the prototypic hematopoietic stem cell model and then gives a brief overview of the in vitro and vivo features of the former, emphasizing on their immunoregulatory properties and their hematopoiesis-supporting role. In addition, the qualitative and quantitative characteristics of BM MSCs within the context of a defective microenvironment, such as the one characterizing Myelodysplastic Syndromes are described and the potential involvement of these cells in the pathophysiology of the disease is discussed. Finally, emerging clinical applications of BM MSCs in the field of hematopoietic stem cell transplantation are reviewed and potential hazards from MSC use are outlined.

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Bone marrow mesenchymal stem cells: biological properties ...

Mesenchymal and haematopoietic stem cells form a unique …

ai, In vivo self-renewal of adult bone marrow CD45Nes-GFP+ cells in secondary transplants. a, Scheme showing the experimental paradigm. be, Primary ossicles showing numerous -galactosidase+ osteoblasts derived from CD45Nes-GFP+ cells (b, blue; d, e, dark deposits, arrowheads) but none from CD45Nes-GFP cells (c); haematopoietic areas (b, e; circled by dashed line) were detected only in the former group and frequently associated with GFP+ cells (e, green). f, Secondary ossicle showing numerous -galactosidase+ osteoblasts derived from CD45Nes-GFP+ cells (blue) and also haematopoietic areas (circled by dashed line). g, CD45+ haematopoietic cells (red) localized near Nes-GFP+ (green) cells in the ossicles; cell nuclei have been stained with DAPI (blue); grid, 50 m per square. h, i, Secondary ossicles yielded 8,557 537 GFP+ spheres (h) that generated Col2.3+ osteoblasts (i; blue precipitates). jm, Adult nestin+ MSCs contribute to endochondral lineages. jl, Femoral sections from 11-month-old Nes-creERT2/RCE:loxP double-transgenic mice 8 months after tamoxifen treatment showing the contribution of adult nestin+ cells to bone-lining osteoblasts (j), osteocytes (k; asterisks indicate GFP+ cells, arrowheads indicate GFP osteocytes) and collagen 1 type 2+ (red) chondrocytes (l). m, GFP+ (green) perivascular cells (asterisk) identical in frequency, morphology and distribution to Nes-GFP+ cells and osteoblasts (arrowhead) co-stained with anti-GFP antibodies (red). n, o, Bone marrow section of Nes-Gfp/Col2.3-cre/R26R triple-transgenic mouse showing X-gal+ osteoblasts (dark precipitates), GFP+ (green) and CD31+ vascular endothelial cells (red); Col2.3+ osteoblasts localized near Nes-GFP+ perivascular cells are indicated with arrowheads. p, q, Immunostaining for osterix (red) in trabecular bone section of a 5-week-old Nes-Gfp (green) mouse. g, jm, oq, Nuclei have been stained with DAPI (blue). j, l,m, p, q, Bone (b) margins are indicated with dashed lines. b, c, f, i, n, Bright field; g, j, k, p, q, fluorescence; d, e, h, l, m, o, overlapped fluorescence and bright field. Scale bars: 100 m (cf, h, i); 20 m (jq).

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Mesenchymal and haematopoietic stem cells form a unique ...

The Bone Marrow Niche for Haematopoietic Stem Cells

a. HSCs are found mainly adjacent to sinusoids throughout the bone marrow,,,, where endothelial cells and mesenchymal stromal cells promote HSC maintenance by producing SCF, CXCL12,,, and likely other factors. Similar cells may also promote HSC maintenance around other types of blood vessels, such as arterioles. The mesenchymal stromal cells can be identified based on their expression of Lepr-Cre, Prx1-Cre, Cxcl12-GFP, or Nestin-GFP transgene in mice and similar cells are likely to be identified by CD146 expression in humans. These perivascular stromal cells, which likely include Cxcl12-abundant Reticular (CAR) cells, are fated to form bone in vivo, express Mx-1-Cre and overlap with CD45/Ter119PDGFR +Sca-1+ stromal cells that are highly enriched for MSCs in culture. b. It is likely that other cells also contribute to this niche, likely including cells near bone surfaces in trabecular rich areas. Other cell types that regulate HSC niches include sympathetic nerves,, non-myelinating Schwann cells (which are also Nestin+), macrophages, osteoclasts, extracellular matrix ,, and calcium. Osteoblasts do not directly promote HSC maintenance but do promote the maintenance and perhaps the differentiation of certain lymphoid progenitors by secreting Cxcl12 and likely other factors,,,. Early lineage committed progenitors thus reside in an endosteal niche that is spatially and cellularly distinct from HSCs.

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The Bone Marrow Niche for Haematopoietic Stem Cells

Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

This week I treated a patient with adipose SVF stem cells to augment a low stem cell yield from bone marrow. I dont do this often, as the quality of fat stem cells for orthopedic applications like arthritis is much less. We do use fat for an occasional structural graft in various procedures. Today I wanted to give you a clinicians eye view of the harvest procedures for both stem cell types that you wont see elsewhere, so let Fat vs Bone Marrow Stem Cells begin.

In summary, harvesting fat in a mini-liposuction is a violent affair, harvesting stem cells from a bone marrow aspirate is like an advanced blood draw. Let me explain.

In order to get fat through a mini-liposuction you need to first use a scalpel to open a small incision in the skin. This isnt at all required for a bone marrow aspiration as the needle is just inserted into the skin like any other needle. In the liposuction, the whole goal is disrupting large amounts of normal tissue. In fact, the stem cells live around the blood vessels, so you have to chew up as many blood vessels in the fat as possible to get a good stem cell yield. This involves placing a small wand like device under the skin and into the fat and moving it back and forth (through much resistance) to break apart large sections of tissue. The bone marrow aspiration simply involves directing the needle under the x-ray to the desired area of bone. The needle is then turned back and forth a few times to enter the bone (which is like hard plastic instead of cement). At this point in the liposuction the doctor must continue to break up large swaths of tissue with suction, sucking the broken tissue and blood vessels into a syringe. On the other hand, in the bone marrow aspiration the doctor simply draws the bone marrow aspirate (which looks like blood) into the syringe like a common blood draw.

The complication rates for these two procedures tell the rest of the story. Mini-liposuction procedures have surgical style complication rates of 3-10%, while bone marrow aspiration complication rates are so rare that only a handful occurred in more than 20,000 procedures in one U.K. registry. The upshot? It always makes me chuckle (in a bad way) when I hear fat stem cell advocates claim that a bone marrow aspiration procedure is so invasive. Youhavent seen invasive until youve seen a lipo-suction!

Go here to see the original:
Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

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