Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used) or allogeneic (the stem cells come from a donor). 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. 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.

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.[1][2]

Indications for stem cell transplantation are as follows:

Many recipients of HSCTs are multiple myeloma[3] or leukemia patients[4] 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[5] who have lost their stem cells after birth. Other conditions[6] 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.

A total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide in 2006, 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).[7] In 2009, according to the World Marrow Donor Association, stem cell products provided for unrelated transplantation worldwide had increased to 15,399 (3,445 bone marrow donations, 8,162 peripheral blood stem cell donations, and 3,792 cord blood units).[8]

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 function 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 (graft-versus-host disease) 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.[9]

However, for others 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.[10] 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.[11]

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.[12] 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.[13][14][15]

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.[16]

As of 2013[update], there were at least two commercialized allogeneic cell therapies, Prochymal and Cartistem.[17]

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[18] are now the most common source of stem cells for allogeneic 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.[19]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.[20]: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.[21][22] Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants.[23] 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.[20][22]

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.[24] 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. 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.[25][26] 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.[27]

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).[27]

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.[28]

Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HCST) 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.[13][14] In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.[29]

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al.,[30] 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.[31]) 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).[32][33][34] In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.[34]

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.[33] G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors.[33] There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.[35]

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.[34]

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.[34] 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.[34] Bone pain receded post-donation to 26 percent of patients 2 days post-donation, 6 percent of patients one week post-donation, and <2 percent 1 year post-donation. Donation is not recommended for those with a history of back pain.[34] Other symptoms observed in more than 40 percent of donors include myalgia, headache, fatigue, and insomnia.[34] These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3 percent of donors.[34]

In one metastudy that incorporated data from 377 donors, 44 percent of patients reported having adverse side effects after peripheral blood HSCT.[35] Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.[35]

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.[34] Donors were not observed to have higher than normal rates of cancer with up to 48 years of follow up.[34] 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.[33] 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.[33]

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.[36][37][38][39][40] Math later pioneered the use of bone marrow transplants in the treatment of leukemia.[40]

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.[41]

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.[42] 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.[43]

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).[44]

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.[45]

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.[45] 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.[46] 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.[47][48] 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.[49] 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.[50] 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.[51][52]

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.[53]

Since McAllister's 1997 report on a patient with multiple sclerosis (MS) who received a bone marrow transplant for CML,[54] there have been over 600 reports of HSCTs performed primarily for MS.[55] 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".[55]

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Hematopoietic stem cell transplantation - Wikipedia, the ...

Bone Marrow Stem Cells Comments Off on Hematopoietic stem cell transplantation – Wikipedia, the … | October 23rd, 2015

Corresponding Author: Joshua M. Hare, MD, The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Biomedical Research Bldg/Room 908, PO Box 016960 (R-125), Miami, FL 33101 (jhare@med.miami.edu).

Published Online: November 6, 2012. doi:10.1001/jama.2012.25321

Author Contributions:Dr Hare had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hare, Gerstenblith, DiFede Velazquez, George, Mendizabal, McNiece, Heldman.

Acquisition of data: Hare, Fishman, Gerstenblith, DiFede Velazquez, Zambrano, Suncion, Tracy, Johnston, Brinker, Breton, Davis-Sproul, Byrnes, George, Lardo, Mendizabal, Lowery, Wong Po Foo, Ruiz, Amador, Da Silva, McNiece, Heldman.

Analysis and interpretation of data: Hare, Fishman, Zambrano, Suncion, Tracy, Ghersin, Lardo, Schulman, Mendizabal, Altman, Ruiz, Amador, Da Silva, McNiece, Heldman.

Drafting of the manuscript: Hare, Fishman, Ghersin, Mendizabal, Ruiz, Amador, Heldman.

Critical revision of the manuscript for important intellectual content: Hare, Fishman, Gerstenblith, DiFede Velazquez, Suncion, Tracy, Johnston, Brinker, Breton, Davis-Sproul, Schulman, Byrnes, Geroge, Lardo, Mendizabal, Lowery, Rouy, Altman, Wong Po Foo, Ruiz, Da Silva, McNiece, Heldman.

Statistical analysis: Hare, Mendizabal, McNiece, Heldman.

Obtained funding: Hare, Lardo.

Administrative, technical, or material support: Hare, DiFede Velazquez, Zambrano, Suncion, Ghersin, Johnston, Breton, Davis-Sproul, Schulman, Byrnes, Lowery, Rouy, Altman, Wong Po Foo, Da Silva, McNiece, Heldman.

Study supervision: Hare, Fishman, Gerstenblith, Tracy, George, Schulman, Altman, Da Silva, McNiece, Heldman.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hare reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, having equity interest in Vestion Inc, and being a consultant for Kardia. Dr George reported serving on the board of GE Healthcare, consulting for ICON Medical Imaging, and receiving trademark royalties for fluoroperfusion imaging. Mr Mendizabal is an employee of EMMES Corporation. Drs Rouy, Altman, and Wong Po Foo are employees of Biocardia Inc. Dr McNiece reported being a consultant and board member of Proteonomix Inc. Dr Heldman reported having a patent for cardiac cell-based therapy, receiving research support from and being a board member of Biocardia, and having equity interest in Vestion Inc. No other authors reported any financial disclosures.

Funding/Support: This study was funded by the US National Heart, Lung, and Blood Institute (NHLBI) as part of the Specialized Centers for Cell-Based Therapy U54 grant (U54HL081028-01). Dr Hare is also supported by National Institutes of Health (NIH) grants RO1 HL094849, P20 HL101443, RO1 HL084275, RO1 HL107110, RO1 HL110737, and UM1HL113460. The NHLBI provided oversight of the clinical trial through the independent Gene and Cell Therapy Data and Safety Monitoring Board (DSMB). Biocardia Inc provided the Helical Infusion Catheters for the conduct of POSEIDON.

Role of the Sponsors: The NHLBI, NIH, and Biocardia Inc had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the NHLBI Gene and Cell Therapy DSMB, the patients who participated in this trial, the bone marrow donors, the staff of the cardiac catheterization laboratories at the University of Miami Hospital and The Johns Hopkins Hospital. Erica Anderson, MA (EMMES Corporation), provided data management and Hongwei Tang, MD (TeraRecon Inc), provided consultation regarding CT imaging analysis. Ms Anderson received compensation for her contribution via the Specialized Centers for Cell-Based Therapy grant. Dr Tang did not receive any compensation for his contribution.

This article was corrected for errors on July 19, 2013.

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JAMA | Comparison of Allogeneic vs Autologous Bone Marrow ...

Bone Marrow Stem Cells Comments Off on JAMA | Comparison of Allogeneic vs Autologous Bone Marrow … | October 9th, 2015

A transplant of the stem cells that form in bone marrow can help people recover from certain types of cancers and blood and bone marrow disorders, but having a bone marrow or stem cell transplant can require a donation from someone.

The bones of the body are hollow and in the centre especially in the flat bones such as the breastbone and pelvis can be found a soft tissue known as bone marrow. This sponge-like substance produces stem cells. These are immature cells that constantly divide to produce new cells, some of which grow into mature blood cells used by the body. These include:

Stem cells need to divide rapidly to make millions of blood cells every day. Without these stem cells it would be impossible to survive.

People who have a condition that damages bone marrow may not have enough stem cells to produce normal blood cells. This can occur if there is a type of bone marrow failure or a genetic blood or immune system disorder.

In other cases, treating people with certain types of cancer sometimes requires giving very high doses of chemotherapy to kill the cancer cells in the body. Whole body radiotherapy may also be used to kill off the cancer cells. However, these treatments can also kill healthy cells in the body, including the stem cells in bone marrow.

People who may need a bone marrow transplant include those with:

The collected stem cells are added to a solution that is put into the body by using a drip, similar to receiving a blood transfusion. These cells enter the bloodstream and then travel to the bones, where they can start producing blood cells again. In people who have cancer, this is performed the day after treatment with chemotherapy or radiotherapy ends.

Because having a transplant involves being given different medicines and blood transfusions as well as the transplant itself, the patient may be given a central line, or central venous catheter. An operation will be performed to insert a thin tube through the skin near the collarbone and into a large vein near the heart.

The transplant itself isn't painful, but the person will need to remain in hospital for between 5 to 6 weeks while their bone marrow recovers, allowing time for the donated stem cells to settle in and start producing new cells. Antibiotics are often given to limit the risk of infection, which is particularly high during this period and the reason why the person may be placed in isolation. Blood transfusions may also be necessary until the bone marrow is making enough new blood cells. The person will also be monitored to ensure the stem cells have been accepted.

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Bone marrow (stem cell) transplant and donation

Bone Marrow Stem Cells Comments Off on Bone marrow (stem cell) transplant and donation | August 30th, 2015

People usually volunteer to donate stem cells for an allogeneic transplant either because they have a loved one or friend who needs a match or because they want to help people. Some people give their stem cells so they can get them back later for an autologous transplant.

People who want to donate stem cells or join a volunteer registry can speak with their doctors or contact the National Marrow Donor Program to find the nearest donor center. Potential donors are asked questions to make sure they are healthy enough to donate and dont pose a risk of infection to the recipient. For more information about donor eligibility guidelines, contact the National Marrow Donor Program or the donor center in your area (see the To learn more section for contact information).

A simple blood test is done to learn the potential donors HLA type. There may be a one-time, tax-deductible fee of about $75 to $100 for this test. People who join a volunteer donor registry will most likely have their tissue type kept on file until they reach age 60.

Pregnant women who want to donate their babys cord blood should make arrangements for it early in the pregnancy, at least before the third trimester. Donation is safe, free, and does not affect the birth process. For more, see the section called How umbilical cord blood is collected.

If a possible stem cell donor is a good match for a recipient, steps are taken to teach the donor about the transplant process and make sure he or she is making an informed decision. If a person decides to donate, a consent form must be signed after the risks of donating are fully discussed. The donor is not pressured take part. Its always a choice.

If a person decides to donate, a medical exam and blood tests will be done to make sure the donor is in good health.

This process is often called bone marrow harvest, and its done in an operating room. The donor is put under general anesthesia (given medicine to put them into a deep sleep so they dont feel pain) while bone marrow is taken. The marrow cells are taken from the back of the pelvic (hip) bone. A large needle is put through the skin and into the back of the hip bone. Its pushed through the bone to the center and the thick, liquid marrow is pulled out through the needle. This is repeated several times until enough marrow has been taken out (harvested). The amount taken depends on the donors weight. Often, about 10% of the donors marrow, or about 2 pints, are collected. This takes about 1 to 2 hours. The body will replace these cells within 4 to 6 weeks. If blood was taken from the donor before the marrow donation, its often given back to the donor at this time.

After the bone marrow is harvested, the donor is taken to the recovery room while the anesthesia wears off. The donor may then be taken to a hospital room and watched until fully alert and able to eat and drink. In most cases, the donor is free to leave the hospital within a few hours or by the next morning.

The donor may have soreness, bruising, and aching at the back of the hips and lower back for a few days. Over-the-counter acetaminophen (Tylenol) or non-steroidal anti-inflammatory drugs (such as aspirin, ibuprofen, or naproxen) are helpful. Some people may feel tired or weak, and have trouble walking for a few days. The donor might be told to take iron supplements until the number of red blood cells returns to normal. Most donors are back to their usual schedule in 2 to 3 days. But it could take 2 or 3 weeks before they feel completely back to normal.

There are few risks for donors and serious complications are rare. But bone marrow donation is a surgical procedure. Rare complications could include anesthesia reactions, infection, transfusion reactions (if a blood transfusion of someone elses blood is needed this doesnt happen if you get your own blood), or injury at the needle insertion sites. Problems such as sore throat or nausea may be caused by anesthesia.

Allogeneic stem cell donors do not have to pay for the harvesting because the recipients insurance company usually covers the cost.

Once the cells are collected, they are filtered through fine mesh screens. This prevents bone or fat particles from being given to the recipient. For an allogeneic or syngeneic transplant, the cells may be given to the recipient through a vein soon after they are harvested. Sometimes they are frozen, such as when the donor lives far away from the recipient.

For several days before starting the donation process, the donor is given a daily injection (shot) of filgrastim (Neupogen). This is a growth-factor drug that causes the bone marrow to make and release stem cells into the blood. Filgrastim can cause some side effects, the most common being bone pain and headaches. These may be helped by over-the-counter acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (like aspirin or ibuprofen). Nausea, sleeping problems, low-grade (mild) fevers, and tiredness are other possible effects. These go away once the injections are finished and collection is completed.

Blood is removed through a catheter (a thin, flexible plastic tube) that is put in a large vein in the arm or chest. Its then cycled through a machine that separates the stem cells from the other blood cells. The stem cells are kept while the rest of the blood is returned to the donor through the same catheter. This process is called apheresis (a-fur-REE-sis). It takes about 2 to 4 hours and is done as an outpatient procedure. Often the process needs to be repeated daily for a few days, until enough stem cells have been collected.

Possible side effects of the catheter can include trouble placing the catheter in the vein, a collapsed lung from catheter placement, blockage of the catheter, or infection of the catheter or at the area where it enters the vein. Blood clots are another possible side effect. During the apheresis procedure donors may have problems caused by low calcium levels from the anti-coagulant drug used to keep the blood from clotting in the machine. These can include feeling lightheaded or tingly, and having chills or muscle cramps. These go away after donation is complete, but may be treated by giving the donor calcium supplements.

The process of donating cells for yourself (autologous stem cell donation) is pretty much the same as when someone donates them for someone else (allogeneic donation). Its just that in autologous stem cell donation the donor is also the recipient, giving stem cells for his or her own use later on. For some people, there are a few differences. For instance, sometimes chemotherapy (chemo) is given before the filgrastim is used to tell the body to make stem cells. Also, sometimes it can be hard to get enough stem cells from a person with cancer. Even after several days of apheresis, there may not be enough for the transplant. This is more likely to be a problem if the patient has had certain kinds of chemo in the past, or if they have an illness that affects their bone marrow.

Sometimes a second drug called plerixafor (Mozobil) is used along with filgrastim in people with non-Hodgkin lymphoma or multiple myeloma. This boosts the stem cell numbers in the blood, and helps reduce the number of apheresis sessions needed to get enough stem cells. It may cause nausea, diarrhea, and sometimes, vomiting. There are medicines to help if these symptoms become a problem. Rarely the spleen can enlarge and even rupture. This can cause severe internal bleeding and requires emergency medical care. The patient should tell the doctor right away if they have any pain in their left shoulder or under their left rib cage which can be symptoms of this emergency.

Parents can donate their newborns cord blood to volunteer or public cord blood banks at no cost. This process does not pose any health risk to the infant. Cord blood transplants use blood that would otherwise be thrown away.

After the umbilical cord is clamped and cut, the placenta and umbilical cord are cleaned. The cord blood is put into a sterile container, mixed with a preservative, and frozen until needed.

Remember that if you want to donate or bank (save) your childs cord blood, you will need to arrange it before the baby is born. Some banks require you to set it up before the 28th week of pregnancy, although others accept later setups. Among other things, you will be asked to answer health questions and sign a consent form.

Many hospitals collect cord blood for donation, which makes it easier for parents to donate. For more about donating your newborns cord blood, call 1-800-MARROW2 (1-800-627-7692) or visit Be the Match.

Privately storing a babys cord blood for future use is not the same as donating cord blood. Its covered in the section called Other transplant issues.

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Whats it like to donate stem cells?

Bone Marrow Stem Cells Comments Off on Whats it like to donate stem cells? | August 29th, 2015

Date: 01 Aug 2015

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Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5M), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20M. We further revealed that TSA (1 and 5M) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

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Effects of Tanshinone IIA on osteogenic differentiation of ...

Bone Marrow Stem Cells Comments Off on Effects of Tanshinone IIA on osteogenic differentiation of … | August 1st, 2015

You will have a low white blood cell count after your treatment. This means you are more at risk of getting an infection. You are likely to get an infection from the normally harmless bacteria we all have in our digestive systems and on our skin.

To stop this from happening your nurse may give you tablets called gut sterilisers (antibiotics) and mouthwashes. And they will encourage you to have a shower each day.

You are also at risk of infection from food. The nurses on the ward will tell you and your relatives about the food you can and can't eat. The rules vary from hospital to hospital but you may be told that

Your room will be thoroughly cleaned every day. Your visitors will be asked to wash their hands before they come into your room. They may also have to wear disposable gloves and aprons. Visitors with coughs and colds are not allowed. Some hospitals don't allow you to have plants or flowers in your room because bacteria and fungi can grow in the soil or water, and may cause infection.

Even with all these precautions, most people do get an infection at some point and need to have antibiotics. You can help yourself by trying to do your mouth care properly and getting up to shower and have your bed changed even on the days you don't feel too good.

After a transplant you will have lost immunity to diseases you were vaccinated against as a child. The team caring for you will advise you about the immunisations you need and when. You should only have inactivated immunisations and not live ones. To lower the risk of you getting any of these infections it is important that all your family have the flu vaccine and any children have all their immunisations.

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Side effects of bone marrow and stem cell transplants ...

Bone Marrow Stem Cells Comments Off on Side effects of bone marrow and stem cell transplants … | July 23rd, 2015

High levels of active TGF- in the bone marrow and abnormalities in bone remodeling are associated with multiple skeletal disorders. Genetic mutations in the TGF- signaling pathway cause premature activation of matrix latent TGF- and may manifest with various skeletal defects. There are additional diseases that result in high levels of active TGF-, which may contribute to the pathology. Here, we discuss how abnormal TGF- signaling results in uncoupled bone remodeling, mainly by loss of site-directed recruitment of MSCs that causes aberrant bone formation. Direct or indirect inhibition of TGF- signaling may provide potential therapeutic options for these disorders.

Genetic disorders. The critical role of TGF-1 in the reversal phase of bone remodeling is demonstrated by the range of skeletal disorders resulting from mutations in genes involved in TGF-1 signaling. Camurati-Engelmann disease (CED), characterized by a fusiform thickening of the diaphysis of the long bones and skull, is caused by mutations in TGFB1 that result in premature activation of TGF-1 (7174). Approximately 11 different TGFB1 mutations have been identified from families affected by CED (75, 76). All of the mutations are located in the region encoding LAP, either destabilizing LAP disulfide bridging or affecting secretion of the protein, both of which increase TGF-1 signaling, as confirmed by in vitro cell cultures and mouse models. Bone histology sections from patients with CED show decreased trabecular connectivity despite normal bone histomorphometric parameters with respect to osteoblast and osteoclast numbers (76, 77), suggestive of uncoupled bone remodeling. In vitro, the ratio of active to total TGF-1 in conditioned medium from cells expressing the CED mutant TGF-1 is significantly higher and enhances MSC migration (18). Targeted recruitment of MSCs to the bone-remodeling site is likely disrupted, secondary to loss of a TGF- gradient.

Elevations in TGF- signaling have also been observed in many genetic connective tissue disorders with craniofacial, skeletal, skin, and cardiovascular manifestations, including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). MFS is caused by mutations in fibrillin and often results in aortic dilation, myopia, bone overgrowth, and joint laxity. Fibrillin is deposited in the ECM and normally binds TGF-, rendering it inactive. In MFS, the decreased level of fibrillin enhances TGF- activity (78). LDS is caused by inactivating mutations in genes encoding TRI and TRII (79). Physical manifestations include arterial aneurysms, hypertelorism, bifid uvula/cleft palate, and bone overgrowth resulting in arachnodactyly, joint laxity, and scoliosis. Pathologic analyses of affected tissue suggest chronically elevated TGF- signaling, despite the inactivating mutation (79). The mechanism of enhanced TGF- signaling remains under investigation. SGS is caused by mutations in the v-ski avian sarcoma viral oncogene homolog (SKI; refs. 80, 81) and causes physical features similar to those of MFS plus craniosynostosis. SKI negatively regulates SMAD-dependent TGF- signaling by impeding SMAD2 and SMAD3 activation, preventing nuclear translocation of the SMAD4 complex, and inhibiting TGF- target gene output by competing with p300/CBP for SMAD binding and recruiting transcriptional repressor proteins, such as mSin3A and HDACs (8284).

The neurocutaneous syndrome neurofibromatosis type 1 (NF1) has been noted to have skeletal features similar to those of CED, MFS, and LDS, including kyphoscoliosis, osteoporosis, and tibial pseudoarthrosis. Hyperactive TGF-1 signaling has been implicated as the primary factor underlying the pathophysiology of the osseous defects in Nf1fl/Col2.3Cre mice, a model of NF1 that closely recapitulates the skeletal abnormalities found in human disease (85). The exact mechanisms mediating mutant neurofibrominassociated enhancement of TGF- production and signaling remain unknown.

Osteoarthritis. While genetic disorders are rare, they have provided critical insight into the pathophysiology of more common disorders. Uncoupled bone remodeling accompanies the onset of osteoarthritis. TGF-1 is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis (86). High levels of active TGF-1 induced formation of nestin+ MSC clusters via activation of ALK5-SMAD2/3. MSCs underwent osteoblast differentiation in these clusters, leading to formation of marrow osteoid islets. Transgenic expression of active TGF-1 in osteoblastic cells alone was sufficient to induce osteoarthritis, whereas direct inhibition of TGF- activity in subchondral bone attenuated the degeneration of articular cartilage. Knockout of Tgfbr2 in nestin+ MSCs reduced osteoarthritis development after ACLT compared with wild-type mice, which confirmed that MSCs are the target cell population of TGF- signaling. High levels of active TGF-1 in subchondral bone likely disrupt the TGF- gradient and interfere with targeted migration of MSCs. Furthermore, mutations of ECM proteins that bind to latent TGF-s, such as small leucine-rich proteoglycans (87) and fibrillin (88), or mutations in genes involved in activation of TGF-, such as in CED (76) and LDS (89), are associated with high osteoarthritis incidence. Osteoblast differentiation of MSCs in aberrant locations appears histologically as subchondral bone osteoid islets and alters the thickness of the subchondral plate and calcified cartilage zone, changes known to be associated with osteoarthritis (90, 91). A computer-simulated model found that a minor increase in the size of the subchondral bone (1%2%) causes significant changes in the mechanical load properties on articular cartilage, which likely leads to degeneration (86). Importantly, inhibition of the TGF- signaling pathway delayed the development of osteoarthritis in both mouse and rat models (86).

MSCs in bone loss. Aging leads to deterioration of tissue and organ function. Skeletal aging is especially dramatic: bone loss in both women and men begins as early as the third decade, immediately after peak bone mass. Aging bone loss occurs when bone formation does not adequately compensate for osteoclast bone resorption during remodeling. Age-associated osteoporosis was previously believed to be due to a decline in survival and function of osteoblasts and osteoprogenitors; however, recent work by Park and colleagues found that mature osteoblasts and osteoprogenitors are actually nonreplicative cells and require constant replenishment from bone marrow MSCs (92). When MSCs fail to migrate to bone-resorptive sites or are unable to commit and differentiate into osteoblasts, new bone formation is impaired. Therefore, insufficient recruitment of MSCs, or their differentiation to osteoblasts, at the bone remodeling surface may contribute to the decline in bone formation in the elderly.

There are multiple hypotheses regarding the decreased osteogenic potential of MSCs during aging. For example, during aging, the bone marrow environment has an increased concentration of ROS and lipid oxidation that may decrease osteoblast differentiation, yet increase osteoclast activity (93, 94). MSCs also undergo senescence, which decreases proliferative capacity and contributes to decreased bone formation (95, 96). Cellular senescence involves the secretion of a plethora of factors, including TGF-, which induces expression of cyclin-dependent kinase inhibitors 2A and 2B (p16INK4A and p15INK4B, respectively; refs. 97).

Microgravity experienced by astronauts during spaceflight causes severe physiological alterations in the human body, including a 1%2% loss of bone mass every month during spaceflight (98). Several studies have shown decreases in osteoblastic markers of bone formation and increases in bone resorption (99101). The underlying molecular mechanisms responsible for the apparent concurrent decrease in bone formation and increase in bone resorption remain under investigation. Work by the McDonald group suggests that bone remodeling may become uncoupled under zero-gravity conditions secondary to decreased RhoA activity and resultant changes in actin stress fiber formation (102). In modeled microgravity, cultured human MSCs exhibit disruption of F-actin stress fibers within three hours of initiation of microgravity; the fibers are completely absent after seven days. RhoA activity is significantly reduced, and introduction of an adenoviral construct expressing constitutively active RhoA can reverse the elimination of stress fibers, significantly increasing markers of osteoblast differentiation (102). Under zero-gravity conditions, RhoA is unable to bind to its receptor, and a sufficient number of MSCs may not be able to migrate correctly to the bone-resorptive site for osteoblast differentiation, ultimately leading to bone loss with every cycle of remodeling.

Bone metastases are a frequent complication of cancer and often have both osteolytic and osteoblastic features, indicative of dysregulated bone remodeling. The importance of the bone marrow microenvironment contributing to the spread of cancer was first described in 1889 (103), postulating that tumor cells can grow only if they are in a conducive environment. Activation of matrix TGF- during bone remodeling plays a central role in the initiation of bone metastases and tumor expansion by regulating osteolytic and prometastatic factors (reviewed in refs. 104110). For example, TGF- can induce osteoclastic bone destruction by upregulating tumor cell expression of PTHrP and IL-11. Additionally, upregulation of CXCR4 by TGF- may home cancer cells to bones.

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JCI - Bone marrow mesenchymal stem cells and TGF- ...

Bone Marrow Stem Cells Comments Off on JCI – Bone marrow mesenchymal stem cells and TGF- … | July 16th, 2015

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Haematopoietic stem cells and early lymphoid progenitors ...

Bone Marrow Stem Cells Comments Off on Haematopoietic stem cells and early lymphoid progenitors … | July 12th, 2015

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. 2012 October 18;367(16):10.1056/NEJMoa1203517.

Outcomes after Transplantation, According to Study Group

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

Bone Marrow Stem Cells Comments Off on Peripheral-blood stem cells versus bone marrow from … | July 8th, 2015

With Brigham and Womens Hospital and Boston Childrens Hospital, Dana-Farber has performed thousands of stem cell/bone marrow transplants for adult and pediatric patients with blood cancers and other serious illnesses.

Whats the difference between these two terms? As it turns out, the only real distinction is in the method of collecting the stem cells.

Lets start with the basics.

Stem cells are versatile cells with the ability to divide and develop into many other kinds of cells.

Hematopoietic stem cells produce red blood cells, which deliver oxygen throughout the body; white blood cells, which help ward off infections; and platelets, which allow blood to clot and wounds to heal.

While chemotherapy and/or radiation therapy are essential treatments for the majority of cancer patients, high doses can severely weakenand even wipe outhealthy stem cells. Thats where stem cell transplantation comes in.

Stem cell transplantation is a general term that describes the procedures performed by the Adult Stem Cell Transplantation Program at Dana-Farber/Brigham and Womens Cancer Center and the Pediatric Stem Cell Transplantation Program at Dana-Farber/Boston Childrens Cancer and Blood Disorders Center.

Stem cells for transplant can come from bone marrow or blood.

When stem cells are collected from bone marrow and transplanted into a patient, the procedure is known as a bone marrow transplant. If the transplanted stem cells came from the bloodstream, the procedure is called a peripheral blood stem cell transplantsometimes shortened to stem cell transplant.

Whether you hear someone talking about a stem cell transplant or a bone marrow transplant, they are still referring to stem cell transplantation. The only difference is where in the body the transplanted stem cells came from. The transplants themselves are the same.

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Stem Cell vs. Bone Marrow Transplant: Whats the ...

Bone Marrow Stem Cells Comments Off on Stem Cell vs. Bone Marrow Transplant: Whats the … | July 3rd, 2015

Having someone elses marrow or stem cells is called a donor transplant, or an allogeneic transplant. This is pronounced al-lo-jen-ay-ik.

The donors bone marrow cells must match your own as closely as possible. The most suitable donor is usually a close relative, such as a brother or sister. It is sometimes possible to find a match in an unrelated donor. Doctors call this a matched unrelated donor (MUD). To find out if there is a suitable donor for you, your doctor will contact The Anthony Nolan Bone Marrow Register and other UK based and international bone marrow registers.

To make sure that your donors cells match, you and the donor will have blood tests. These are to see how many of the proteins on the surface of their blood cells match yours. This is called tissue typing or HLA matching. HLA stands for human leucocyte antigen.

Once you have a donor and are in remission, you have high dose chemotherapy either on its own or with radiotherapy. A week later the donor goes into hospital and their stem cells or marrow are collected. You then have the stem cells or bone marrow as a drip through your central line.

If you've had a transplant from a donor, there is a risk of graft versus host disease (GVHD). This happens because the transplanted stem cells or bone marrow contain cells from your donor's immune system. These cells can sometimes recognise your own tissues as being foreign and attack them. This can be an advantage because the immune cells may also attack any leukaemia cells left after your treatment.

Acute GVHD starts within 100 days of the transplant and can cause

If you develop GVHD after your transplant, your doctor will prescribe medicines to damp down this immune reaction. These are called immunosuppressants.

Chronic GVHD starts more than 100 days after the transplant and you may have

Your doctor is likely to suggest that you stay out of the sun because GVHD skin rashes can often get worse in the sun.

There is detailed information about graft versus host disease in the section about coping physically with cancer.

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Bone marrow or stem cell transplants for AML | Cancer ...

Bone Marrow Stem Cells Comments Off on Bone marrow or stem cell transplants for AML | Cancer … | June 26th, 2015

A new study from the Forsyth Institute is helping to shed light on latent tuberculosis and the bacteria's ability to hide in stem cells. Some bone marrow stem cells reside in low oxygen (hypoxia) zones. These specialized zones are secured as immune cells and toxic chemicals cannot reach this zone. Hypoxia- activated cell signaling pathways may also protect the stem cells from dying or ageing. A new study led by Forsyth Scientist Dr. Bikul Das has found that Mycobacterium tuberculosis (Mtb) hijack this protective hypoxic zone to hide intracellular to a special stem cell type. The study was published online on June 8th in the American Journal of Pathology.

Mtb, the causative organism of tuberculosis, infects nearly 2.2 billion people worldwide and causes 1.7 million annual deaths. This is largely attributed to the bacteria's ability to stay dormant in the human body and later resurface as active disease. Earlier research at Forsyth revealed that Mtb hides inside a specific stem cell population in bone marrow, the CD271+ mesenchymal stem cells. However, the exact location of the Mtb harboring stem cells was not known.

"From our previous research, we learned that cancer stem cells reside in the hypoxic zones to maintain self-renewal property, and escape from the immune system" said Bikul Das, MBBS, PhD, Associate Research Investigator at the Forsyth Institute, and the honorary director of the KaviKrishna laboratory, Guwahati, India. "So, we hypothesized that Mtb, like cancer, may also have figured out the advantage of hiding in the hypoxic area."

To test this hypothesis, Dr. Das and his collaborators at Jawarharlal Nehru Univeristy (JNU), New Delhi, and KaviKrishna Laboratory, Indian Institute of Technology, Guwahati, utilized a well-known mouse model of Mtb infection, where months after drug treatment, Mtb remain dormant for future reactivation. Using this mouse model of dormancy, scientists isolated the special bone marrow stem cell type, the CD271+ mesenchymal stem cells, from the drug treated mice. Prior to isolation of the stem cells, mice were injected with pimonidazole, a chemical that binds specifically to hypoxic cells. Pimonidazole binding of these cells was visualized under confocal microscope and via flow cytometry. The scientists found that despite months of drug treatment, Mtb could be recovered from the CD271+ stem cells. Most importantly, these stem cells exhibit strong binding to pimonidazole, indicating the hypoxic localization of the stem cells. Experiments also confirmed that these stem cells express a hypoxia activated gene, the hypoxia inducible factor 1 alpha (HIF-1 alpha).

To confirm the findings in clinical subjects, the research team, in collaboration with KaviKrishna Laboratory, the team isolated the CD271+ stem cell type from the bone marrow of TB infected human subjects who had undergone extensive treatment for the disease. They found that not only did the stem cell type contain viable Mtb, but also exhibit strong expression of HIF-1alpha. To their surprise, the CD271+ stem cell population expressed several fold higher expression of HIF-1alpha than the stem cell type obtained from the healthy individuals.

"These findings now explain why it is difficult to develop vaccines against tuberculosis," said Dr. Das. "The immune cells activated by the vaccine agent may not be able to reach the hypoxic site of bone marrow to target these "wolfs-in-stem-cell-clothing".

The success of this international collaborative study is now encouraging the team to develop a Forsyth Institute/KaviKrishna Laboratory global health research initiative to advance stem cell research and its application to global health issues including TB, HIV and oral cancer, all critical problems in the area where KaviKrishna Laboratory is located.

###

Das is the co-senior and co-corresponding author of the study, Rakesh Bhatnagar, PhD, professor of biotechnology, JNU, New Delhi, is the co-senior author of the study. Ms. Jaishree Garhain, a PhD student of Dr. Das and Dr. Bhatnagar, is the first author of the study. Other members of the team are Ms. Seema Bhuyan, Dr. Deepjyoti Kalita, and Dr. Ista Pulu. The research was funded by the KaviKrishna Foundation (Sualkuchi, India), the Laurel Foundation (Pasadena, California), and Department of Biotechnology, India.

About The Forsyth Institute

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Tuberculosis bacteria hide in the low oxygen niches of ...

Bone Marrow Stem Cells Comments Off on Tuberculosis bacteria hide in the low oxygen niches of … | June 20th, 2015

Key Messages:

Although a stem cell transplant (sometimes called a bone marrow transplant) is an effective treatment for several types of cancer, it can cause a number of different side effects. The type and intensity of these side effects vary from person to person and depend on the kind of transplant performed, the person's overall health, and other factors. Your health care team will work with you to prevent side effects or manage any that occur. This is called palliative or supportive care and is an important part of your overall treatment plan. Be sure to talk with your health care team about any side effects you experience, including new symptoms or a change in symptoms.

The two most serious side effects of stem cell transplantation are infection and graft-versus-host disease.

Infection

The chemotherapy and/or radiation therapy given before a stem cell transplant weakens a persons immune system, lowering the bodys defenses against bacteria, viruses, and fungi. That means stem cell recipients are especially vulnerable to infection during this early period of treatment.

Although most people think the greatest risk of infection is from visitors or food, most infections that occur during the first few weeks after a transplant are caused by organisms that are already in the patient's lungs, sinuses, skin, and intestines. Fortunately, most of these infections are relatively easy to treat with antibiotics.

The reduced immunity of the early transplant period lasts about two weeks, after which the immune system is back to near full strength and can keep most common germs at bay without the help of medications. This is true for both autologous (AUTO) transplant recipients (who receive their own stem cells) and allogeneic (ALLO) transplant recipients (who receive stem cells from another person).

However, a risk of serious infection remains for ALLO transplant recipients because they are given anti-rejection drugs. These drugs suppress the immune system to prevent the body from rejecting the donors stem cells. However, this low immunity also leaves the body more at risk for infection. This risk increases when more anti-rejection drugs are needed. Your treatment team will work with you to prevent and manage infections.

Graft-versus-host disease

People who have an ALLO transplant are also at risk of developing a post-transplant illness called graft-versus-host disease (GVHD). It occurs when the transplanted stem cells recognize the patients body as foreign and attack it, causing inflammation. GVHD ranges from mild to life-threatening. AUTO transplant recipients do not face this risk because the transplanted stem cells come from their own bodies.

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Side Effects of Stem Cell/Bone Marrow Transplantation ...

Bone Marrow Stem Cells Comments Off on Side Effects of Stem Cell/Bone Marrow Transplantation … | May 13th, 2015

Stem cell transplant (also known as bone marrow transplant or BMT) is an established treatment for many cancers and blood diseases once considered incurable. For some types of blood diseases, transplantation is the standard of care. For others, it is only considered if other treatments have not been successful. Ongoing advances in stem cell transplant are expanding its availability and improving outcomes for patients, young and old.

Here at the University of Chicago Medicine, the brightest minds in medicine are ready to meet the needs of all patients considering a stem cell transplant. We offer the latest promising approaches in blood and bone marrow stem cell transplant. Our team is known -- and recognized -- for our experience and expertise in:

We provide outstanding and compassionate care in a patient-centered environment. The Stem Cell Transplant Unit, located on the top floor of the Center for Care and Discovery, offers the newest technology as well as many thoughtful patient and family amenities. The unit integrates both inpatient and outpatient stem cell transplant care services in one convenient location.

As part of the internationally recognized University of Chicago Comprehensive Cancer Center (UCCCC), we participate in national clinical trials testing new and emerging therapies. A primary site for early-phase clinical trials, we offer our patients access to more new treatment protocols than any other hospital in the region.

As a leading center for advanced care, the University of Chicago Medicine attracts patients from throughout the region, the country and around the world. We provide customized services for patients who travel from other countries. For more information, contact the Center for International Patients.

In the late 1940s, University of Chicago researcher Dr. Leon Jacobson discovered that he could save a mouse, whose bone marrow and spleen had been destroyed with radiation, by transplanting healthy spleen tissue from another mouse. The donated tissue repopulated the marrow and restored production of the blood cells. This groundbreaking work influenced many scientists investigating bone marrow transplant for humans, including the winner of the 1990 Nobel Prize in Physiology or Medicine.

For information about stem cell transplant for children and teens, visit the Pediatric Stem Cell Transplant page on the University of Chicago Comer Childrens Hospital website.

UCH_008151 (19)

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Blood and Bone Marrow Stem Cell Transplantation - The ...

Bone Marrow Stem Cells Comments Off on Blood and Bone Marrow Stem Cell Transplantation – The … | April 27th, 2015

Repairing Chronic Muscle Tears with Stem Cells
Chronic muscle tears like hamstring pulls and shoulder rotator cuff muscles are tough to heal. Research suggests that injecting bone marrow stem cells into the area may solve that problem.

By: Chris Centeno

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Repairing Chronic Muscle Tears with Stem Cells - Video

Bone Marrow Stem Cells Comments Off on Repairing Chronic Muscle Tears with Stem Cells – Video | April 22nd, 2015

What can mesenchymal stem cells do?

Mesenchymal stem cells (MSCs) are an example of tissue or 'adult' stem cells. They are multipotent, meaning they can produce more than one type of specialized cell of the body, but not all types. MSCs make the different specialized cells found in the skeletal tissues. For example, they can differentiate or specialize into cartilage cells (chondrocytes), bone cells (osteoblasts) and fat cells (adipocytes). These specialized cells each have their own characteristic shapes, structures and functions, and each belongs in a particular tissue.

Some early research suggested that MSCs might also differentiate into many different types of cells that do not belong to the skeletal tissues, such as nerve cells, heart muscle cells, liver cells and endothelial cells, which form the inner layer of blood vessels. These results have not been confirmed to date. In some cases, it appears that the MSCs fused together with existing specialized cells, leading to false conclusions about the ability of MSCs to produce certain cell types. In other cases, the results were an artificial effect caused by chemicals used to grow the cells in the lab.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

MSCs were originally found in the bone marrow. There have since been many claims that they also exist in a wide variety of other tissues, such as umbilical cord blood, adipose (fat) tissue and muscle. It has not yet been established whether the cells taken from these other tissues are really the same as, or similar to, the mesenchymal stem cells of the bone marrow.

The bone marrow contains many different types of cells. Among them are blood stem cells (also called hematopoietic stem cells; HSCs) and a variety of different types of cells belonging to a group called mesenchymal cells. Only about 0.001-0.01% of the cells in the bone marrow are mesenchymal stem cells.

It is fairly easy to obtain a mixture of different mesenchymal cell types from adult bone marrow for research. But isolating the tiny fraction of cells that are mesenchymal stem cells is more complicated. Some of the cells in the mixture may be able to form bone or fat tissues, for example, but still do not have all the properties of mesenchymal stem cells. The challenge is to identify and pick out the cells that can both self-renew (produce more of themselves) and can differentiate into three cell types bone, cartilage and fat. Scientists have not yet reached a consensus about the best way to do this.

No treatments using MSCs are yet available. However, several possibilities for their use in the clinic are currently being explored.

Bone and cartilage repair The ability of MSCs to differentiate into bone cells called osteoblasts has led to their use in early clinical trials investigating the safety of potential bone repair methods. These studies are looking at possible treatments for localized skeletal defects (damage at a particular place in the bone).

Other research is focussed on using MSCs to repair cartilage. Cartilage covers the ends of bones and allows one bone to slide over another at the joints. It can be damaged by a sudden injury like a fall, or over a long period by a condition like osteoarthritis, a very painful disease of the joints. Cartilage does not repair itself well after damage. The best treatment available for severe cartilage damage is surgery to replace the damaged joint with an artificial one. Because MSCs can differentiate into cartilage cells called chondrocytes, scientists hope MSCs could be injected into patients to repair and maintain the cartilage in their joints. Researchers are also investigating the possibility that transplanted MSCs may release substances that will tell the patients own cells to repair the damage.

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Mesenchymal stem cells: the 'other' bone marrow stem cells ...

Bone Marrow Stem Cells Comments Off on Mesenchymal stem cells: the ‘other’ bone marrow stem cells … | April 17th, 2015

Miami, FL (PRWEB) April 09, 2015

Global Stem Cells Group subsidiary Adimarket has been named the Latin America distributor for bone marrow technology leader Ranfac Corporation. The announcement coincides with Global Stem Cells Groups most recent expansion plans in Latin America, an ongoing effort to meet the regions growing demands for access to regenerative medicine and stem cell therapies.

Ranfac manufactures state-of-the-art surgical, radiology, hematology and orthopedic products including a range of bone marrow aspiration needles, each designed to provide a simple means of harvesting marrow from the patients sternum (breastbone) or the iliac crest (part of the pelvic bone) for a variety of medical procedures. Ranfacs newest technology is designed to harvest high quality bone marrow derived cells without the need for centrifugation.

Ranfac bone marrow technology is used by physicians and medical specialists worldwide. Global Stem Cells Group Advisory Board member Joseph Purita, M.D., a pioneer in the use of laser and stem cell therapies in orthopedic medicine, endorses Ranfacs bone marrow aspiration technology. Purita recently joined other specialists including fellow GSCG Advisory Board member David B Harrell, PhD, Brt, OF, FAARM, FRIPH, DABRM, in a trial study and white paper collaboration on Ranfacs new, non-centrifugal bone marrow technology.

Both Purita and Harrell endorse the Ranfac systems enhanced safety and ability to increase the concentrations of stem and progenitor cells during the bone marrow aspiration process.

Our ground-breaking hematology and orthopedic products for bone marrow access, aspiration, stem cell harvesting and biopsy procedures are designed to provide a more efficient result during critical procedures, says Ranfac CEO Barry Zimble. We believe that this is the perfect time to team with Global Stem Cells Group as our distribution partner in Latin Americas fast-growing medical community.

The collaboration between Global Stem Cells Group and Ranfac is another step toward GSCGs commitment to expanding its presence in communities that need and deserve access to cutting-edge regenerative medicine, not only in Latin America but also worldwide.

The timing couldnt be better to represent Ranfacs cutting edge bone marrow technology in the emerging markets of Latin America. Global is always looking to provide patients and practitioners with the best resources that regenerative medicine has to offer says Ricardo DeCubas, Global Stem Cells Group co-founder and Regenestem CEO.

For more information visit the Global Stem Cells Group website, email bnovas@stemcellsgroup.com, or call 305-224-1858.

About Global Stem Cells Group:

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Global Stem Cells Group Subsidiary Adimarket Named Latin American Distributor for Ranfac Bone Marrow Technology

Bone Marrow Stem Cells Comments Off on Global Stem Cells Group Subsidiary Adimarket Named Latin American Distributor for Ranfac Bone Marrow Technology | April 10th, 2015

Stem Cell Research in Cardiology
Bharat Book Bureau provides the report, on Stem Cell Research in Cardiology. The study is segmented by Source (Allogenic and Autogenic) and by Type (Bone Marrow Stem Cells, Embryonic...

By: Bharat Book

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Stem Cell Research in Cardiology - Video

Bone Marrow Stem Cells Comments Off on Stem Cell Research in Cardiology – Video | April 10th, 2015

Telomeres are short stretches of repeated nucleotides that protect the ends of chromosomes. In somatic cells, these protective sequences become shorter with each cellular replication until a critical length is reached, which can trigger cell death.

In actively replicating cells such as germ cells, embryonic stem cells, and blood stem cells of the bone marrow, the enzyme telomerase replenishes these protective caps to ensure adequate replication. Cancer cells also seem to have the ability to activate telomerase, which allows them to keep dividing indefinitely, with dire consequences for the patient. However, according to a study published April 10 in the JNCI: Journal of the National Cancer Institute, the extent to which cancer cells can utilize telomerase may depend on which variants of the genes related to telomerase activity are expressed in an individual's cells.

Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle. Thus, a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow the presumably causal association of telomere length and cancer mortality to be studied.

To perform this analysis, Line Rode, M.D., Ph.D., of the Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, and colleagues, used data from two prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 64,637 individuals followed from 1991-2011. Participants completed a questionnaire and had a physical examination and blood drawn for biochemistry, genotyping, and telomere length assays.

For each subject, the authors had information on physical characteristics such as body mass index, blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables. In addition to the measure of telomere length for each subject, three single nucleotide polymorphisms of TERC, TERT, and OBFC1 were used to construct a score for the presence of telomere shortening alleles.

A total of 7607 individuals died during the study, 2420 of cancer. Overall, as expected, decreasing telomere length as measured in leukocytes was associated with age and other variables such as BMI and smoking and with death from all causes, including cancer. Surprisingly, and in contrast, a higher genetic score for telomere shortening was associated specifically with decreased cancer mortality, but not with any other causes of death, suggesting that the slightly shorter telomeres in the cancer patients with the higher genetic score for telomere shortening might be beneficial because the uncontrolled cancer cell replication that leads to tumor progression and death is reduced.

The authors conclude, "We speculate that long telomeres may represent a survival advantage for cancer cells, allowing multiple cell divisions leading to high cancer mortality."

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Contact info:

Stig E. Bojesen, M.D., D.M.Sc., stig.egil.bojesen@regionh.dk

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Telomeres and cancer mortality: The long and the short of it

Bone Marrow Stem Cells Comments Off on Telomeres and cancer mortality: The long and the short of it | April 10th, 2015

Rice University and Texas Children's Hospital scientists are using stem cells from amniotic fluid to promote the growth of robust, functional blood vessels in healing hydrogels.

In new experiments, the lab of bioengineer Jeffrey Jacot combined versatile amniotic stem cells with injectable hydrogels used as scaffolds in regenerative medicine and proved they enhance the development of vessels needed to bring blood to new tissue and carry waste products away.

The results appear in the Journal of Biomedical Materials Research Part A.

Jacot and his colleagues study the use of amniotic fluid cells from pregnant women to help heal infants born with congenital heart defects. Such fluids, drawn during standard tests, are generally discarded but show promise for implants made from a baby's own genetically matched material.

He contends amniotic stem cells are valuable for their ability to differentiate into many other types of cells, including endothelial cells that form blood vessels.

"The main thing we've figured out is how to get a vascularized device: laboratory-grown tissue that is made entirely from amniotic fluid cells," Jacot said. "We showed it's possible to use only cells derived from amniotic fluid."

In the lab, researchers from Rice, Texas Children's Hospital and Baylor College of Medicine combined amniotic fluid stem cells with a hydrogel made from polyethylene glycol and fibrin. Fibrin is a biopolymer critical to blood clotting, cellular-matrix interactions, wound healing and angiogenesis, the process by which new vessels branch off from existing ones. Fibrin is widely used as a bioscaffold but suffers from low mechanical stiffness and rapid degradation. Combining fibrin and polyethylene glycol made the hydrogel much more robust, Jacot said.

The lab used vascular endothelial growth factor to prompt stem cells to turn into endothelial cells, while the presence of fibrin encouraged the infiltration of native vasculature from neighboring tissue.

Mice injected with fibrin-only hydrogels showed the development of thin fibril structures, while those infused with the amniotic cell/fibrin hydrogel showed far more robust vasculature, according to the researchers.

Similar experiments using hydrogel seeded with bone marrow-derived mesenchymal cells also showed vascular growth, but without the guarantee of a tissue match, Jacot said. Seeding with endothelial cells didn't work as well as the researchers expected, he said.

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Amniotic stem cells demonstrate healing potential

Bone Marrow Stem Cells Comments Off on Amniotic stem cells demonstrate healing potential | April 10th, 2015