February 1, 2011 by

Limb Transplants Facilitated by Bone Marrow Stem Cells

Kuo et al. Plast Reconstr Surg. 2011 Feb;127(2):569-79.

Composite tissue allografts are usually transplants of anatomical structures that contain multiple types of tissues. We have seen numerous high-profile examples of human composite tissue allografts such as whole hands, faces, and arms. While advancement of surgical techniques have made such transplants a reality, immunologically-mediated rejection remains a formidable problem.

Mesenchymal stem cells are particularly interesting in terms of an “adjuvant” to transplant immune suppression for several reasons.

Firstly, mesenchymal stem cells are known to be immune modulatory. It is known that these cells suppress activation of dendritic cells (which are involved in stimulating immune responses). Mesenchymal stem cells also inhibit CD4 and CD8 T cell responses. This is beneficial in that the CD4 cell coordinates immune attacks and the CD8 T cell causes cytotoxicity of organs that are being rejected. Perhaps even more interestingly, mesenchymal stem cells are known to stimulate production of T regulatory cells. These are cells of the immune system that suppress other immune cells and are associated with prolongation of transplanted graft survival. At a molecular level how the mesenchymal stem cells modulate the immune system seems to involve several biological modulators. Mesenchymal stem cells express the enzyme indomlamine 2,3 deoxygenase, which metabolizes tryptophan. T cells are highly dependent on tryptophan for activation. Mesenchymal stem cells have been demonstrated to actively induce T cell death by localized starvation of tryptophan. Additionally, mesenchymal stem cells produce various immune suppressive cytokines such as Leukemia Inhibitory Factor (LIF), IL-10, TGF-b, and soluble HLA-G. One interesting method by which mesenchymal stem cells suppress the immune system is by expression of surface-bound immune cell killing molecules such as Fas ligand. Evidence supporting the immune suppressive effects of mesenchymal stem cells includes the ability of these cells to control pathological immunity such as graft versus host disease, multiple sclerosis, and Type 1 diabetes.

Secondly, mesenchymal stem cells are known to be angiogenic. This is the process of new blood vessel formation. Subsequent to organ transplantation it is essential that the transplanted organ receive a proper blood supply. While ligation of major blood vessels is performed during the transplantation surgery, proper integration of the donor and recipient blood vessels is an important factor in graft survival.

Thirdly, mesenchymal stem cells have the ability to repair injured organs. There is a substantial amount of injury that occurs as a result of the organ procurement, transportation , and implantation procedure. This injury is termed ischemia/reperfusion injury. The extent of ischemia reperfusion injury contributes more to graft long term survival as compared even to MHC mismatches. As a result of the injury chemoattractants are generated that cause homing of stem cells into the injured organ. It is possible that these stem cells actually contribute to healing and perhaps regeneration of the injured organ.

In the publication discussed, the authors used a porcine model of hind limb transplantation. Four groups of pigs were used:

Group 1: Four untreated recipients

Group 2: Three recipients that received mesenchymal stem cells alone

Group 3: Five recipients that received cyclosporine alone

Group 4: Three recipients that received cyclosporine, irradiation, and mesenchymal stem cells

It was found that treatment with mesenchymal stem cells along with irradiation and cyclosporine A resulted in significant increases in allograft survival as compared with other groups (>120 days; p = 0.018).

Flow cytometric analysis revealed a significant increase in the percentage of CD4/CD25 and CD4/FoxP3 T cells in both the blood and graft in the mesenchymal stem cell/irradiation/cyclosporine A group.

These preliminary data suggest that addition of mesenchymal stem cells to the combination of cyclosporine and irradiation resulted in significant allograft survival. Unfortunately in Group 3 they did not add irradiation so it is impossible to know whether the graft survival was caused by the irradiation or by the mesenchymal stem cells.

Previous collaborations between Thomas Ichim of Medistem and Hao Wang’s group from University of Western Ontario, Canada suggests that a radioresistant element in free bone transplants contributes to prolonged allograft survival. It may be possible that the radioresistant cells were mesenchymal stem cells in nature. This is an area in which future studies are definitely warranted.

Filed Under: Adult Stem Cells, Bone Marrow, News, Stem Cell Research Tagged With: , , , ,
January 31, 2011 by

Nine Patients with Crohn’s Disease Treated by Intravenous Administration of Mesenchymal Stem Cells

Marjolijn et al. Gut 59:1662

Mesenchymal stem cells are known to be suppressive to immune cells such as T cells, dendritic cells, and natural killer cells. Studies have demonstrated that patients suffering from the immune disease graft versus host enter remission after administration of donor or third party mesenchymal stem cells. One of the manifestations of graft versus host disease is inflammation of the colon, resembling autoimmune colitis and Crohn’s disease.

Some of the previous studies investigating this condition have demonstrated therapeutic effects of mesenchymal stem cells on colonic inflammation. Given this rationale, a recent paper examined the effects of autologous mesenchymal stem cells in the treatment of Crohn’s disease refractory to steroids, immune suppressants, and biologics.

50-100 ml of bone marrow cells were isolated from family members or third-party donors and expanded in vitro. Cells where grown to administer two doses, a week a part, of 1-2 x 10(6) cells per kg body weight. Patients were treated by intravenous administration and followed up for 6 months.

MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224-378). Three patients showed clinical response (CDAI decrease ≥70 from baseline) 6 weeks post-treatment. Additionally, 3 other patient required surgery, presumably as a result of disease progression.

These data demonstrate that intravenous administration of bone marrow mesenchymal stem cells appears to be safe for treatment of Crohn’s disease, however larger studies are necessary to determine whether statistically significant efficacy exists.

Filed Under: Crohn's Disease, News, Stem Cell Research Tagged With: , , , , ,
January 31, 2011 by

New Cell That Keeps Stem Cells in the Bone Marrow

Chow et al. J Exp Med.

When a bone marrow transplant is performed, the bone marrow cells of the donor are injected intravenously into the recipient and somehow find their way back into the bone marrow of the recipient. The mechanism known to be responsible for this has always been cited as being SDF-1 (also called CXCL12) produced by bone marrow “stromal” cells. This mechanism is of fundamental importance to stem cell therapists for two reasons:

Firstly, stem cells are known to be recruited by injured tissue, which produces SDF-1. This has been explained as one of the mechanisms by which both cardiac and brain infarcts cause recruitment of endogenous and exogenous stem cells to the area of injury.

Secondly, by temporarily interrupting the production of SDF-1 or recognition of SDF-1 by CXCR-4, drugs such as Mozibil have been developed which are used in the mobilization of stem cells for patients who mobilize poorly in response to G-CSF.

In a paper that we view as groundbreaking, scientists found that one of the key cells in the bone marrow that produces SDF-1 is the CD169 positive macrophage. The scientists examined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced production of SDF-1 by the bone marrow.

They also found that depletion of CD169(+) MΦ, which spares BM MOs, was sufficient to induce stem cell mobilization. This depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor.

Thus it appears that specific macrophage subsets play specific roles in the bone marrow stem cell system. It may be possible to use these macrophages as therapeutic agents to cause recruitment of stem cells into injured organs.

Filed Under: Adult Stem Cells, Bone Marrow, News Tagged With: , , ,
January 28, 2011 by

Arteriocyte gets FDA approval to begin critical limb ischemia clinical trial

Medcity News

Critical limb ischemia is an advanced form of peripheral artery disease that causes hundreds of thousands of amputations per year. This condition is attractive to stem cell intervention because even a marginal improvement in circulation may be enough to prevent amputation. Previous work from Japan and Mike Murphy’s group at Indiana has demonstrated that use of patient’s bone marrow stem cells can effectively reduce ulcers and increase circulation.

Today the Ohio company Arteriocyte has received approval from the U.S. Food and Drug Administration to begin a Phase 1 clinical trial for the treatment of critical limb ischemia. The clinical trial will investigate the use of Arteriocyte’s Magellan device. The device concentrates stem cells and blood platelets during surgeries. These concentrated cells can be injected into patients, boosting the body’s ability to repair itself. The device is already used in about 6,000 surgeries per month, according to the company.

In addition to critical limb ischemia, Arteriocyte plans to begin clinical trials assessing Magellan’s ability to treat cardiovascular disease, and the clinical setting of orthopedics and tissue repair during 2011, according to the statement.

Arteriocyte CEO Don Brown stated “The synergy that the Magellan technology brings to our core efforts is a device that enables rapid bedside processing of tissue — blood or bone marrow — that delivers back to the surgeon a concentrated injectate of those cells for use as the surgeon deems appropriate.”

Other approaches to treatment of critical limb ischemia include the use of “universal donor” stem cells. These have an advantage in the sense that bone marrow does not need to be harvested from the patient that is being treated. In contrast, stem cells are extracted from healthy donors, expanded in tissue culture, and sold as a “stem cell drug.” This is the approach that Medistem is pursuing with its Endometrial Regenerative Cells. Other companies working on universal donor stem cells for critical limb ischemia include Pluristem, which derives its stem cells from the placenta and expands them using a proprietary bioreactor.

Universal donor stem cells from the bone marrow are currently being developed by Athersys, Osiris, and Allocure.

Currently the most advanced critical limb ischemia clinical trials are from the companies Harvest and Bio-Met, which also have devices. The company Aastrom is also involved in critical limb ischemia, they are using a bioreactor to expand patient’s own bone marrow derived stem cells. Aldagen is also using bone marrow derived stem cells for critical limb ischemia, these ones are purified on the basis of aldehyde dehydrogenase expression.

Filed Under: News Tagged With: , , ,
January 4, 2011 by

Male-Pattern Baldness Found Rooted in Stem Cells

Amanda Chan, MyHealthNewsDaily Staff Writer

A new discovery regarding the presence of stem cells in males with androgenetic alopecia (male-pattern baldness) has led to hope that the disease may be treatable. It was previously believed that people who suffered from baldness also had a depleted number of hair follicle stem cells, meaning that new hair growth would not be possible. However, this new discovery has shown that the number of stem cells present in bald areas and non-bald areas is equal; the difference is a depleted number of hair follicle progenitor cells.

The implication for this discovery are if scientists are able to coax the present stem cells into developing into hair follicle progenitor cells, they would be able to regrow hair. The only FDA approved baldness treatments; Rogaine and Propecia do not have the ability to regrow cells. Propecia works by inhibiting testosterone’s effect on hair follicles, disrupting its ability to decrease the size of hair follicles.

http://www.livescience.com/health/male-pattern-baldness-stem-cells-110104.html

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
January 3, 2011 by

Advanced Cell Technology Receives FDA Clearance For Clinical Trials Using Embryonic Stem Cells to Treat Age-Related Macular Degeneration

Business Wire

Advanced Cell Technology, a biotechnology company based in Marlborough, Massachusetts which specializes in the development and commercialization of cell therapies for the treatment of a variety of diseases has been awarded FDA clearance to begin a clinical trial implementing human embryonic stem cells (hESCs) to treat Age-Related Macular Degeneration (AMD).

AMD has two forms, wet and dry, dry AMD being the most prominent, accounting for almost 90% of AMD cases. Dry AMD is the leading cause of blindness in people over the age of 55. Blindness results from the loss of retinal pigment epithelial cells, a single layer of six hexagonal cells just outside the neurosensory retina, responsible for nourishing the macula, the part of the eye responsible for high acuity vision.

The Phase I/II clinical trial will be performed at the Jules Stein Eye Institute at UCLA and the Opthalmology Department at the Stanford School of Medicine. The trial will determine the safety and efficiency of the RPE cells following sub-retinal transplantation. The proposed therapy uses RPE cells derived from hESCs to replace the diminished levels of RPE cells in the diseased patient. The company hopes to show that the RPE cells can be injected into to the retinal space in order to slow or halt the progression of AMD.

http://www.businesswire.com/news/home/20110103005348/en/Advanced-Cell-Technology-Receives-FDA-Clearance-Clinical

Filed Under: News, Stem Cell Research Tagged With: , , , , ,
January 1, 2011 by

Study Shows Patient’s Own Stem Cells Help Stroke Recovery: 16 Treated Patients Improve in Comparison to 36 Controls

Lee et al Stem Cells 28:1099
Stroke is caused by blocked circulation to parts of the brain usually as a result of a blood clot. Outcomes of stroke are generally proportional to the length of time the circulation was blocked and to the amount of brain tissue injury and death. Although the introduction of “clot busters” has improved outcomes in these patients, substantially morbidity and mortality still occurs. Numerous pharmaceutical approaches have been attempted in the treatment of stroke, both from the perspective of inhibiting tissue damage, and more recently trying to stimulate regeneration of injured brain tissue. To date clinical progress in this area has been relatively insignificant. In fact, in the pharmaceutical industry the condition of stroke has been referred to as a “graveyard for biotechs”.
One potentially promising treatment for stroke would be to augment the body’s own repair processes through activation of stem cells that are either pre-existing in the body, or through administration of stem cells either directly into the damaged brain tissue or areas associated with the damaged brain tissue. Rationale for this includes observations that stem cells from the bone marrow called endothelial progenitor cells are known to enter circulation in patients with stroke. A study from Dunac et al in France demonstrated that patients who have a higher degree of stem cells in circulation after a stroke have a better neurological outcome in comparison to patients who have lower numbers of circulating stem cells. In rats which are given a stroke experimental by ligation of one of the arteries that feeds the brain, called the middle cerebral artery, administration of human or rat stem cells reduces the size of brain damage, as well as causes regeneration of new neurons. Additionally, animal studies have demonstrated that administration of stem cells causes improved behavior as compared to animals receiving control cells or saline.
One reason why there exists a belief in the field that bone marrow derived cells may be capable of generating new neurons is that in female recipients of bone marrow transplant nerve cells have been found that express the Y-chromosome (Weimann et al. Contribution of transplanted bone marrow cells to purkinje neurons in human adult brains Proc Natl Acad Sci USA 100:2088).
In a recent paper (Lee et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099) a group from Korea reported what to date is the largest clinical trial of stem cells in stroke. The investigators used mesenchymal stem cells generated from the bone marrow of the stroke patients. These cells are believed to be capable of generating new neurons, as well as producing growth factors that stimulate the brain to heal itself. Mesenchymal stem cells are currently used in clinical trials in the US and internationally for treatment of graft versus host disease, heart failure, and critical limb ischemia (an advanced form of peripheral artery disease that causes 100-200,000 amputations per year). Advantages of mesenchymal stem cells include: a) ability to be expanded in tissue culture; b) Well-known safety profile; and c) Ability to use between individuals without need for matching.
In the study discussed, the investigators selected 52 patients with a defined type of stroke (non-lacunar infarction within the middle cerebral artery territory). Patients were selected 7 days after the stroke in order to have a standardized level of dysfunction. It was previously published that before 7 days the patient may have a sudden increase or decrease in neurological function, but after 7 days post-stroke the neurological function remains stable.
The investigators extracted 5 ml of bone marrow from 16 patients and expanded the mesenchymal stem cells over a 4 week period. The mesenchymal stem cells were defined as cells expressing the markers CD105 (SH-2) and SH-4. Cells were grown as adherent cells in media containing fetal calf serum. The 16 patients received two administrations of 50 million cells intravenously spread apart by a week.
Patients were followed for an average of 117 weeks, with some patients followed as long as 5-years after the stroke. There was a statistically significant difference in overall survival in the patients that received the mesenchymal stem cells as compared to controls. Specifically, 4 of the 16 patients who received the mesenchymal stem cells passed away during the follow-up period as compared to 21 of the 36 control patients.
In studies of embryonic or fetal stem cells, one of the major concerns is development of tumors. This stems from the fact that administration of embryonic stem cells into immune deficient animals causes tumors called teratomas, and in humans there is at least one documented case of a brain tumor developing in a patient who received fetal derived stem cells. Of the patients administered mesenchymal stem cells, no tumors were detected. This is important because this study has one of the longest follow up periods.
Functional improvements as quantified by the modified Rankin Score were noted in patients receiving stem cells, whereas controls overall suffered a decline in function. Specifically, function was assessed at a median of 3.5 years in the control group and 3.2 years in the mesenchymal stem cell treated group. Function was assessed by doctors where were “blinded” to which patient received stem cells and which patient was in the control group. In the control group 13 of 26 patients had a negative rank, which indicates an improved functional outcome for each patient, whereas 21 patients had a positive rank, which means worse outcome. In contrast, in the treatment group 11 of the 16 patients had a negative rank. The difference between groups reached statistical significance.
In 9 patients of the group that received stem cells, a correlation was studied between the cytokine SDF-1 and functional outcome. Functional outcome was determined both by the modified Rankin score as well as by the Barthel index. A positive correlation was found between levels of SDF-1 at the time of MSC treatment and functional outcome in the patients studied. This protein is known to be involved in recruiting stem cells to the site of injury. Given that in this study the stem cells were administered intravenously and not locally (eg by sterotactic injection), it would be logical that a correlation exist between chemotactic signaling and improved outcome. Currently there are companies such as Juvantis, that are administering plasmids expressing SDF-1 in order to induce homing of endogenous stem cells into cardiac infarcts. It is interesting that the same priniciple may be valid in situations of ischemic stroke. To date no studies have been performed clinically using co-administration of stem cells and SDF-1, however, myoblasts transfected with SDF-1 have been used in a clinical trial in Jordan by the company BioHeart for treatment of heart failure.
One other interesting finding of the study besides lack of ectopic tissue or tumor formation is that no adverse effects were associated with using stem cells grown in fetal calf serum. There has been concern in the literature, particularly the academic literature, that fetal calf serum may induce autoimmunity or sensitization upon second MSC administration. This did not appear to be the case.

Filed Under: Adult Stem Cells, Bone Marrow, News, Stem Cell Research, Stroke Tagged With: , , , , ,
December 31, 2010 by

Differences between Stem Cells from the Placenta and Bone Marrow

Fazekasova et al. Mesenchymal stem cells were historically isolated from the bone marrow as an adherent stem cell population capable of “orthodox” differentiation, meaning that they have ability to become bone, cartilage, and fat. Further research revealed that these cells are also capable of “non-orthodox” differentiation, that is, becoming neurons, hepatocytes, insulin producing cells, and lung cells. Given the high number of growth factors secreted by mesenchymal stem cells, numerous companies have sought to develop therapeutic products from mesenchymal stem cells. For example, Osiris Therapeutics has been developing bone marrow mesenchymal stem cells as a treatment for Graft Versus Host Disease. Athersys has been using bone marrow derived mesenchymal-like cells for treatment of heart disease, and Mesoblast has been using these cells for treatment of bone injury.

A new generation of companies has been focusing other mesenchymal-like cells derived from other tissues. For example, Medistem Inc has identified endometrial regenerative cells (ERC), a type of mesenchymal-like stem cell that is found in the endometrium and appears to have higher ability to produce growth factors that stimulate new blood vessel production as compared to other sources of mesenchymal stem cells. General Biotechnology LLC has been developing tooth derived mesenchymal stem cells for treatment of neurological disorders. Celgene has been using placental-derived mesenchymal stem cells for treatment of critical limb ischemia, a disorder associated with poor circulation of the legs.

Given that there appear to be various sources of mesenchymal stem cells, an important question is how do these cells compare when they are used in experiments side by side. In a paper published this month, placental derived and bone marrow derived mesenchymal stem cells were compared. The scientists found that higher numbers of mesenchymal stem cells could be isolated from the placenta as compared to the bone marrow. Interestingly, placental mesenchymal stem cells were found to be comprised of both fetal and maternal origin.

One of the critical features of mesenchymal stem cells is that they are able to be used without need for matching with the recipient. This is because mesenchymal stem cells are historically known to be “immune privileged”. One of the experiments that the scientists did was to examine whether there is a difference between the bone marrow and placentally derived mesenchymal stem cells in terms of immunogenicity.

Placentally derived mesenchymal stem cells expressed lower levels of the immune stimulatory molecule HLA class I and higher levels of the immune suppressive molecules PDL-1 and CD1a, compared to bone marrow derived mesenchymal stem cells. However, when both cell types were treated with interferon gamma, the placentally derived mesenchymal became much more immune stimulatory as compared to the bone marrow cells. Furthermore it appeared that direct incubation with T cells resulted in higher T cell stimulation with the placental mesenchymal stem cells as compared to the bone marrow cells. Thus from these data it appears that bone marrow derived mesenchymal stem cells are more immune privileged as compare to placental derived cells.

Filed Under: Adult Stem Cells, Bone Marrow, Endometrial Stem Cells, News, Stem Cell Research Tagged With: , , , , , ,
December 30, 2010 by

Men with Type 1 diabetes eventually may have a way to grow their own pancreas transplants

Thomas H. Maugh II, Los Angeles Times

Researchers from Georgetown University Medical Center in Washington DC reported today at the Annual Meeting of the American Society of Cell Biology that sperm contains stem cells capable of becoming beta cells. The beta cells are the insulin producing cells of the pancreas which are damaged/destroyed in patients with Type 1 diabetes.

Conventionally adult stem cells are found in the bone marrow, fat tissue, and cord blood. Recent studies have identified stem cells in places such as menstrual blood (endometrial regenerative cells), hair follicles, and baby teeth. The finding that stem cells from sperm are capable of generating insulin-producing cells has several major implications. For one, males could theoretically bank their own stem cells and use them in the future. Currently transplants with beta cells or pancreatic transplants have the drawback that there are not enough donors and also that the recipient is required to receive life-long immune suppression.

The lead scientist of the finding is biochemist G. Ian Gallicano of Georgetown and his colleagues obtained tissue from human testes from recently deceased donors and placed them in a special growth medium in the laboratory, where they began producing insulin. “These are true pluripotent stem cells,” he said in a statement. When transplanted into the backs of immune-deficient mice, the cells cured diabetes for about a week before dying. More recent results, Gallicano said, show that the researchers are able to produce more insulin-producing cells and keep them alive longer. The challenge, he noted, is to make them survive for very long periods of time in the recipient.

Dr. Gallicano and his team previous published in the peer reviewed journal Stem Cells and Development (Golestaneh et al. Pluripotent stem cells derived from adult human testes Stem Cells Dev. 2009 Oct;18(8):1115-26) that the testes contains spermatogonial stem cells (SSCs) which are capable of converting to embryonic stem (ES)-like cells which can differentiate into all three germ layers and organ lineages.

The importance of the current research is that these stem cells can actually exhibit function when administered to animals. It will be interesting to see if other organ functions may be restored by use of these stem cells.

Filed Under: Diabetes, News, Stem Cell Research Tagged With: , , , ,
December 29, 2010 by

Mechanisms of a New Stem Cell Mobilizer

Jarcome-Galarza et al. J Bone Miner Res.

It is known that the bone marrow contains three main types of stem cells: a) hematopoietic stem cells, which make blood; b) endothelial progenitor cells, which maintain healthy blood vessels; and c) mesenchymal stem cells, which repair a variety of tissues and are capable of producing high amounts of growth factors. After major tissue injury or trauma all three of the bone marrow derived stem cells leave the bone marrow and enter systemic circulation in an attempt to heal the tissue damage. The original compound that was discovered to “mobilize” bone marrow stem cells was granulocyte colony stimulating factor (G-CSF). Studies in mice with lung injury in the late 1970s demonstrated that a lung-derived protein was capable of stimulating bone marrow to multiply and produce higher numbers of granulocytes. It was not until the late 1980s that scientists started injecting purified G-CSF into animals as a method of increasing the number of circulating stem cells. Why would people want to increase circulating stem cells? Commercially one of the main reasons is associated with the process of bone marrow transplantation. In bone marrow transplantation donors were historically required to undergo the painful procedure of bone marrow extraction, which requires an excess of 20 holes to be drilled into their hip bones. Compounds such as G-CSF could be administered to donors in order to make their stem cells enter circulation, and then the stem cells could be isolated from the blood instead of the bone marrow. This makes the procedure a lot less painful and arguably a lot safer. Additionally, the possibility of mobilizing stem cells by administration of a drug has the possibility of artificially increasing stem cell numbers in patients with degenerative diseases in order to attempt to naturally heal the condition.

The clinical use of G-CSF for mobilization and also for increasing granulocytes in the blood has resulted in multibillion dollars per year in sales for companies such as Amgen. Naturally, this has stimulated much interest in the process of how to make stem cells leave the bone marrow. G-CSF stimulates bone marrow stem cell release through several mechanisms. The main mechanism appears to be associated with stimulation of osteoclasts, which cause modulation of the bone marrow structure and physically release the stem cells from their environment. Other mechanisms exist such as breakdown of stromal derived growth factor (SDF-1). This protein is made by the bone marrow and literally keeps the hematopoietic stem cells stuck to the bone. When the bone marrow levels of SDF-1 decrease, the hematopoietic stem cells are no longer “stuck” to the marrow and as a result enter circulation. Yet another mechanism is that G-CSF activates neutrophils to produce various enzymes that cleave proteins on the bone marrow. These cleaved proteins are then recognized by pre-formed antibodies, which activate complement, which causes small holes in the bone marrow and thus releases stem cells.

The second “stem cell mobilizer” to be approved by the FDA is a drug called Mozibil which blocks the interaction between SDF-1 and its receptor CXCR4. This drug was sold by Anormed to Genzyme in a deal worth more than half a billion dollars. Mozibil is a superior stem cell mobilizer to G-CSF in many patients and as a result has rapidly been implemented clinically. Interestingly, it appears that Mozibil causes redistribution of different ratios of hematopoietic, mesenchymal and endothelial progenitor cells than G-CSF.

One of the most recent mobilizers under development is Parathyroid Hormone. This naturally –occurring substance has been demonstrated in clinical trials to mobilize stem cells, but apparently through a mechanism different than G-CSF and Mozibil. Specifically, both of these drugs appear to cause a temporary depletion of the stem cells in the bone marrow, whereas Parathyroid Hormone seems to preserve the stem cells inside of the bone marrow.

A recent paper (Jacome-Galarza et al. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res. 2010 Dec 29) explored the activities of Parathyroid Hormone on osteoclasts in the bone marrow of mice. The authors found that treatment of mice with Parathyroid Hormone for 7 or 14 days increased the number of osteoclastic progenitors in the bone marrow as well as the absolute number of hematopoietic progenitors. These data suggest that the hormone acts not only as a means of stimulating redistribution of hematopoietic stem cells, but also may be involved in directly stimulating their multiplication, possibly through modulating activity of osteoclasts.

Filed Under: News, Stem Cell Research Tagged With: , , , , ,
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