The Amino Acid Valine Helps Maintain Hematopoietic Stem Cell Niches


Hematopoietic stem cells (HSCs) populate our bone marrow and divide throughout our lifetimes to provide the red and white blood cells we need to live. However, during normal, healthy times, only particular HSCs are hard at work dividing and making new blood cells. The remaining HSCs are maintained in a protective dormant state. However, in response to blood loss or physiological stress of some sort, dormant HSCs must wake from their “slumbers” and begin dividing to make the needed blood cells. Such conditions, it turns out, can cause HSCs to experience a good deal of damage to their genomes. A paper that was published in Nature last year by Walter Dagmar and colleagues (Vol 520: pp. 549) showed that repeatedly subjecting mice to conditions that required the activation of dormant HSCs (in this case they injected the mice with polyinosinic:polycytidylic acid or pI:pC to mimic a viral infection and induce a type I interferon response) resulted in the eventual collapse of the bone marrow’s ability to produce new blood cells. The awakened HSCs accumulated such large quantities of DNA damage, that they were no longer able to divide and produce viable progeny. How then can HSCs maintain the integrity of their genomes while still dividing and making new blood cells?

The answer to this question is not completely clear, but a new paper in the December 2 edition of Science magazine provides new insights into HSC physiology and function. This paper by Yuki Taya and others, working in the laboratories of Hiromitsu Nakauchi at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine, and Satoshi Yamazaki from the University of Tokyo, has shown that amino acid metabolism plays a vital role in HSC maintenance. As it turns out, the amino acid concentrations in bone marrow are approximately 100-fold higher than the concentrations of these same amino acids in circulating blood. Taya and others reasoned that such high amino acid concentrations must exist for reasons other than protein synthesis. Therefore, they designed dietary regimens that depleted mice for specific amino acids. Sure enough, when mice were fed valine-depleted diets, the HSCs of those mice lost their ability to repopulate the bone marrow.

Valine
Valine

After only two weeks of valine depletion, several nooks and crannies of the bone marrow – so-called stem cell “niches” – were devoid of HSCs. The bone marrow of such mice was easily reconstituted with HSCs from donor mice without the need for radiation or chemical ablation treatments.

Taya and others found that vascular endothelial stromal cells in the bone marrow secrete valine and that this secreted valine (which, by the way, is a branched-chain amino acid) is integral for maintaining HSC niches.

The excitement surrounding this finding is plain, since using harsh chemicals or radiation to destroy the bone marrow (a procedure known as “myeloablation”) causes premature ageing, infertility, lousy overall health, and other rather unpleasant side effects. Therefore, finding a “kinder, gentler” way to reconstitute the bone marrow would certainly be welcomed by patients and their physicians. However, valine depletion, even though it does not affect sterility, did cause 50% of the mice to die once valine was restored to the diet. This is due to a phenomenon known as the “refeeding effect” which has also been observed in human patients. Such side effects could probably be prevented by gradually returning valine to the diet. Taya and others also showed that cultured human HSCs required valine and another branched-chain amino acid, leucine. Since both leucine and valine are metabolized to alpha-ketoglutatate, which is used as a substrate for DNA-modifying enzymes, these amino acids might exert their effects through epigenetic modifications to the genome.

Alpha-ketoglutarate
Alpha-ketoglutarate

More work is needed in this area, but the Taya paper is a welcomed finding to a vitally important field.

Inhibition of AKT Kinase Increases Umbilical Cord Blood Growth in Culture and Engraftment in Mice


Dr. Yan Liu from the Department of Pediatrics and the Herman B Wells Center for Pediatric Research at the Indiana University School of Medicine in Indianapolis, Indiana and his colleagues have increased the engraftment efficiency of umbilical cord hematopoietic (blood cell-making) stem cells in immunodeficient mice. The technique developed by Lui and his colleagues is simple and increases the proliferation of umbilical cord blood hematopoietic stem cells (UCB-HSCs) in culture, which potentially solves several long-standing problems with umbilical cord blood transplantation.

Umbilical cord blood has been used in the clinic for more than 40 years in hematopoietic stem cell transplantation therapies to treat patients with bone marrow diseases or to reconstitute the bone of those cancer patients who had to have theirs wiped out to cure their leukemia or lymphoma.

One of the problems with umbilical cord blood transplantations, however, is the small amount of material in a typical cord blood collection and, therefore, the small number of hematopoietic stem cells (HSCs) available for transplantation. To ameliorate these shortcomings, hematologists will transplant more than one lot of cord blood (a so-called “double umbilical cord blood transplantation”), which, unfortunately, also increases the risk of immunological rejection (so-called Graft Versus Host response).

A second strategy to get around the low numbers of UCB-HSCs is to expand them in culture, which has proven difficult. However, some experiments have given us more than enough hope to suspect this this is a feasible option (see Flores-Guzmán P, et al., Stem Cells Transl Med. 2013 Nov;2(11):830-8; Bari S., et al., Biol Blood Marrow Transplant. 2015 Jun;21(6):1008-1; Pineault N, Abu-Khader A. Exp Hematol. 2015 Jul;43(7):498-513).

Dr. Lui and his coworkers wanted to examine the role of the signaling protein AKT (also known and protein kinase B) in UCB-HSC expansion in culture. To this end, they used silencing RNAs to knock-down AKT gene expression in cultured UCB-HSCs. AKT knock-down enhanced UCB-HSC quiescence and growth in culture. In a separate experiment, Lui and others treated human UCB-HSCs (so-called CD34+ cells) with a chemical that specifically inhibits AKT activity. Then they subjected these cells to a battery of tests in culture and in laboratory mice.

The results were astounding.  Treatment of human UCB-HSCs did not affect the identity of the HSCs and enhanced their ability to form isolated colonies in cell culture growth tests known as “replating assays.”  Additionally, the short-term inhibition of AKT with drugs also enhanced the ability of UBC-HSCs to repopulate the bone marrow of immunodeficient mice.

ubc-hsc-engraftment-improved-with-akt-inhibition

In summary, inhibition of AKT increases human UCB-HSC quiescence, growth potential, and engraftment in laboratory mice.

These interesting pre-clinical results suggest that AKT inhibitor can increase the expansion of UCB-HSCs in culture and potential increase their tendency of these cells to engraft in patients.

Gamida Cell Announces First Patient with Sickle Cell Disease Transplanted in Phase 1/2 Study of CordIn™ as the Sole Graft Source


An Israeli regenerative therapy company called Gamida Cell specializes in cellular and immune therapies to treat cancer and rare (“orphan”) genetic diseases. Gamida Cell’s main product is called NiCord, which provides patients who need new blood-making stem cells in their bone marrow an alternative to a bone marrow transplant. NiCord is umbilical cord blood that has been expanded in culture. In clinical trials to date, NiCord has rapidly engrafted into patients and the clinical outcomes of NiCord transplantation seem to be comparable to transplantation of peripheral blood.

Gamida Cell’s two products, NiCord and CordIn, as well as some other products under development utilize the company’s proprietary NAM platform technology to expand umbilical cord cells. The NAM platform technology has the remarkable capacity to preserve and enhance the functionality of hematopoietic stem cells from umbilical cord blood. CordIn is an experimental therapy for those rare non-malignant diseases in which bone marrow transplantation is the only currently available cure.

Gamida Cell has recently announced that the first patient with sickle cell disease (SCD) has been transplanted with their CordIn product.  Mark Walters, MD, Director of the Blood and Marrow Transplantation (BMT) Program is the Principal Investigator of this clinical trial. The patient received their transplant at UCSF Benioff Children’s Hospital Oakland.

CordIn, as previously mentioned, is an experimental therapy for rare non-malignant diseases, including hemoglobinopathies such as Sickel Cell Disease and thalassemia, bone marrow failure syndromes such as aplastic anemia, genetic metabolic diseases and refractory autoimmune diseases. CordIn potentially addresses a presently unmet medical need.

“The successful enrollment and transplantation of our first SCD patient with CordIn as a single graft marks an important milestone in our clinical development program. We are eager to demonstrate the potential of CordIn as a transplantation solution to cure SCD and to broaden accessibility to patients with rare genetic diseases in need of bone marrow transplantation,” said Gamida Cell CEO Dr. Yael Margolin. “In the first Phase 1/2 study with SCD, the expanded graft was transplanted along with a non-manipulated umbilical cord blood unit in a double graft configuration. In the second phase 1/2 study we updated the protocol from our first Phase 1/2 study so that patients would be transplanted with CordIn as a standalone graft, which is expanded from one full umbilical cord blood unit and enriched with stem cells using the company’s proprietary NAM technology.”

Somewhere in the vicinity of 100,000 patients in the U.S suffer from SCD; and around 200,000 patients suffer from thalassemia, globally. The financial burden of treating these patients over their lifetime is estimated at $8-9M. Bone marrow transplantation is the only clinically established cure for SCD, but only a few hundred SCD patients have actually received a bone marrow transplant in the last ten years, since most patients were not successful in finding a suitable match. Unrelated cord blood could be available for most of the patients eligible for transplantation, but, unfortunately, the rate of successful engraftment of un-expanded cord blood in these patients is low. Therefore, cord blood is usually not considered for SCD patients. Without a transplant, these patients suffer from very high morbidity and low quality of life.

Eight patients with SCD were transplanted in the first Phase 1/2 study performed in a double graft configuration. This study is still ongoing. Preliminary data from the first study will be summarized and published later this year. A Phase 1/2 of CordIn for the treatment of patients with aplastic anemia will commence later this year.

Genetic Switch to Making More Blood-Making Stem Cells Found


A coalition of stem cell scientists, co-led in Canada by Dr. John Dick, Senior Scientist, Princess Margaret Cancer Centre, University Health Network (UHN) and Professor, Department of Molecular Genetics, University of Toronto, and in the Netherlands by Dr. Gerald de Haan, Scientific Co-Director, European Institute for the Biology of Ageing, University Medical Centre Groningen, the Netherlands, have uncovered a genetic switch that can potentially increase the supply of stem cells for cancer patients who need transplantation therapy to fight their disease.

Their findings were published in the journal Cell Stem Cell and constitute proof-of-concept experiments that may provide a viable new approach to making more stem cells from umbilical cord blood.

“Stem cells are rare in cord blood and often there are not enough present in a typical collection to be useful for human transplantation. The goal is to find ways to make more of them and enable more patients to make use of blood stem cell therapy,” says Dr. Dick. “Our discovery shows a method that could be harnessed over the long-term into a clinical therapy and we could take advantage of cord blood being collected in various public banks that are now growing across the country.”

Currently, all patients who require stem cell transplants must be matched to an adult donor. The donor and the recipient must share a common set of cell surface proteins called “human leukocyte antigens” HLAs. HLAs are found on the surfaces of all nucleated cells in our bodies and these proteins are encoded by a cluster of genes called the “Major Histocompatibility Complex,” (MHC) which is found on chromosome six.

Map of MHC

There are two main types of MHC genes: Class I and Class II.

MHC Functions

Class I MHC contains three genes (HLA-A, B, and C). The three proteins encoded by these genes, HLA-A, -B, & -C, are found on the surfaces of almost all cells in our bodies. The exceptions are red blood cells and platelets, which do not have nuclei. Class II MHC genes consist of HLA-DR, DQ, and DP, and the proteins encoded by these genes are exclusive found on the surfaces of immune cells called “antigen-presenting cells” (includes macrophages, dendritic cells and B cells). Antigen-presenting cells recognize foreign substances in our bodies, grab them and, if you will, hold them up for everyone to see. The cells that usually respond to antigen presentation are immune cells called “T-cells.” T-cells are equipped with an antigen receptor that only binds antigens when those antigens are complexed with HLA proteins.

If you are given cells from another person who is genetically distinct from you, the HLA proteins on the surfaces of those cells are recognized by antigen-presenting cells as foreign substances. The antigen-presenting cells will them present pieces of the foreign HLA proteins on their surfaces, and T-cells will be sensitized to those proteins. These T-cells will them attack and destroy any cells in your body that have those foreign HLA proteins. This is the basis of transplant rejection and is the main reason transplant patients must continue to take drugs that prevent their T-cells from recognizing foreign HLA proteins as foreign.

When it comes to bone marrow transplantations, patients can almost never find a donor whose HLA surface proteins match perfectly. However, if the HLA proteins of the donor are too different from those of the recipient, then the cells from the bone marrow transplant attack the recipient’s cells and destroy them. This is called “Graft versus Host Disease” (GVHD). The inability of leukemia and lymphoma and other patients to receive bone marrow transplants is the unavailability of matching bone marrow. Globally, many thousands of patients are unable to get stem cell transplants needed to combat blood cancers such as leukemia because there is no donor match.

“About 40,000 people receive stem cell transplants each year, but that represents only about one-third of the patients who require this therapy,” says Dr. Dick. “That’s why there is a big push in research to explore cord blood as a source because it is readily available and increases the opportunity to find tissue matches. The key is to expand stem cells from cord blood to make many more samples available to meet this need. And we’re making progress.”

Umbilical cord blood, however, is different from adult bone marrow. The cells in umbilical cord blood are more immature and not nearly as likely to generate GVHD. Therefore, less perfect HLA matches can be used to treat patients in need of a bone marrow transplant. Unfortunately, umbilical cord blood has the drawback of have far fewer stem cells than adult bone marrow. If the number of blood-making (hematopoietic) stem cells in umbilical cord blood can be increased, then umbilical cord blood would become even more useful from a clinical perspective.

There has been a good deal of research into expanding the number of stem cells present in cord blood, the Dick/de Haan teams took a different approach. When a stem cell divides it produces a large number of “progenitor cells” that retain key properties of being able to develop into every one of the 10 mature blood cell types. These progenitor cells, however, have lost the critical ability to self-renew.

Dick and his colleagues analyzed mouse and human models of blood development, and they discovered that a microRNA called miR-125a is a genetic switch that is on in stem cells and controls self-renewal, but gets turned off in the progenitor cells.

“Our work shows that if we artificially throw the switch on in those downstream cells, we can endow them with stemness and they basically become stem cells and can be maintained over the long-term,” says Dr. Dick.

In their paper, Dick and de Haan showed that forced expression of miR-125 increases the number of hematopoietic stem cells in a living animal. Also, miR-125 induces stem cell potential in murine and human progenitor cells, and represses, among others, targets of the MAP kinase signaling pathway, which is important in differentiation of cells away from the stem cell fate. Furthermore, since miR-125 function and targets are conserved in human and mouse, what works in mice might very well work in human patients.

graphical abstract CSC_v9

This is proof-of-concept paper – no human trials have been conducted to date, but these data may be the beginnings of making more stem cells from banked cord blood to cure a variety of blood-based conditions.

Here’s to hoping.

Autologous Stem Cell Transplantation With Complete Ablation of Bone Marrow Delays Progression of Multiple Sclerosis in Small Phase 2 Trial


Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Around 2 million people, worldwide, suffer from MS. MS results from the patient’s immune system attacking the myelin sheath that surrounds nerve axons. These constant and relentless attacks upon the myelin sheath causes “demyelination,” resulting in loss of the sensory and motor function.

Treatment usually required the use of drugs that suppress the immune response. Some of these drugs work better than others, while other patients have forms of MS that do not respond to common MS treatment.

A new report published in the Lancet, has shown that chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) can completely halt clinical relapses of MS and prevent the development of new brain lesions in 23 of 24 MS patients. Patients who participated in this study experienced a prolonged period without the need for ongoing medication. Eight of the 23 patients had a sustained improvement in their disability 7.5 years after treatment. This is the first treatment to produce this level of disease control or neurological recovery from MS, but, unfortunately, treatment related risks limit its widespread use.

There are a few specialist centers that offer MS patients aHSCT. This treatment involves harvesting bone marrow stem cells from the patient, and then employing chemotherapy to suppress the patient’s immune system and essentially partially wipe it out. The isolated bone marrow is then reintroduced into the blood stream to “reset” the immune system and stop it attacking the body. However, a respectable percentage of MS patients relapse after these treatments. Therefore, these treatments must be refined and tweaked to improve their efficacy.

Drs Harold L Atkins and Mark S Freedman from The Ottawa Hospital and the University of Ottawa, Ottawa, Canada, respectively, and their colleagues, tested if complete destruction, rather than suppression, of the immune system during aHSCT could reduce the relapse rate in patients and increase the long-term rates of disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals. All of these subjects had previously undergone standard immunosuppressive therapy, but these treatments had failed to control their MS. These patients all had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100 meters (according to their Expanded Disability Status Scale or EDSS score).

Adkins and Freeman and their coworkers used a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin to wipe out the patient’s bone marrow. Atkins explained that this treatment is “similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system.” After being treated with chemotherapy regimen, the patients’ bone marrow was reconstituted with their previously isolated bone marrow.

This study’s primary outcome was activity-free survival at 3 years, using EDSS scores as the means of measuring MS progression, in addition to scanning for brain lesions, and assessing MS symptoms.

Of the 24 patients enrolled, one (4%) died from liver failure and sepsis caused by the chemotherapy. In the 23 surviving patients, prior to treatment, patients experienced 1.2 relapses per year on average, but after aHSCT, no relapses occurred during the follow-up period (between 4 and 13 years). These clinical outcomes were nicely complemented by an absence of newly detected brain lesions (as assessed by MRI images taken after the treatment). Initially, 24 MRI scans of the brains of all 24 subjects revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion.

Despite the exciting success of this clinical trial, Freedman emphasized the need to interpret these results with caution: “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results. Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centers experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial. Future research will be directed at reducing the risks of this treatment as well as understanding which patients would best benefit from the treatment.”

Dr Jan Dörr, from the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany, made this comment about this clinical trial: “These results are impressive and seem to outbalance any other available treatment for multiple sclerosis. This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period…However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality.”

He added: “So, will this study change our approach to treatment of multiple sclerosis? Probably not in the short-term, mainly because the mortality rate will still be considered unacceptably high. Over the longer term (and) in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonized and optimized, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified.”

Mesoblast Limited Scales Down Phase 3 Trial


Mesoblast Limited announced that the number of subjects treated in their ongoing Phase 3 clinical trial in chronic heart failure (CHF) that is testing their proprietary cell-based medicine MPC-150-IM will be substantially reduced.

CHF is characterized by an enlarged heart, coupled with insufficient blood supply to the organs and extremities of the body. Unfortunately, this is a progressing condition that tends to get worse with time. CHF is caused by many different factors such as chronic high blood pressure, faulty heart valves, infections, or congenital heart problems.

Mesoblast centers their company around the isolation and expansion of so-called mesenchymal precursor cells (MPCs) from bone marrow.  Mesenchymal stem cells are found in many different tissues and organs throughout our bodies.  They play vital roles in maintaining tissue health.  However, relatively speaking, mesenchymal stem cells are rare cells.  They are found around blood vessels and respond to signals associated with tissue damage.  They secrete mediators and growth factors that promote tissue repair and control the immune response to prevent it from going out of control.

Mesoblast uses an array of monoclonal antibodies to isolate primitive mesenchymal stem cells that are actually precursors to mesenchymal stem cells or mesenchymal precursor cells (MPCs).  These cells are then expanded in culture without being differentiated into any other cell type.

Mesoblasts, MPC-150-IM product consists of 150 million MPCs that are injected straight into the heart muscle (hence the moniker, “IM” for intramuscular).  Once in the heart muscle, the MPCs induce the formation of new blood vessels to feed the heart muscle, stimulate resident stem cell populations in the heart to repair the heart muscle, and quell inflammation that can cause scarring and decrease heart function (see Yanping Cheng, et al., Cell Transplantation 22(12): 2299-2309; Jaco H. Houtgraaf, Circulation Research. 2013; 113: 153-166). 

Initially, Mesoblast planned to test their product on 1,165 subjects, but have scaled that number back to approximately 600 patients.

Mesoblast’s development and commercial partner, Teva Pharmacueticals has communicated this reduction in the number of subjects to the US Food and Drug Administration (USFDA). “The reduction in the size of the Phase 3 trial may significantly shorten the time to trial completion,” said Mesoblast CEO Silviu Itescu.

The reduction in the number of patients was due to a proposed change in the primary endpoint of the trial. The revised primary endpoint is now a comparison of recurrent heart failure-related major adverse cardiovascular events (HF-MACE) between patients treated with Mesoblast’s MPC-150-IM cells and the control patients who were not treated with these cells.

Why the change in the primary endpoint? The reason lies in the success that MPC-150-IM cells had their Phase 2 clinical trial. In this trial, a single injection of MPC-150-IM cells successfully prevented HF-MACE over three years. This second, confirmatory study will be conducted in parallel with a patient population that has an identical clinical profile; approximately 600 of them using the same primary endpoint.

In the completed Phase 2 trial, patients treated with MPC-150-IM had no HF-MACE over 36 months of follow-up, compared with 11 HF-MACE in the control group. From this same clinical trial, of those patients who suffered from advanced heart failure (defined by baseline Left Ventricular Systolic Volume being greater than 100 milliliters), 71 percent of the controls (who received no cells) had at least on HF-MACE versus none of those who received a single injection of MPC-150-IM cells. As it turns out, this Phase 2 patient population closely resemble the patients being recruited in the Phase 3 trial.

“Patients with advanced heart failure continue to represent among the largest unmet medical needs, where existing therapies are inadequate and the economic burden is the greatest. The current Phase 3 trial targets this patient population, continues to recruit well across North America, and is now expanding to Europe,” said Itescu.

ASTIC Clinical Trial Fails to Show Clear Advantage to Hematopoietic Stem Cell Transplantation as a Treatment for Crohn’s Disease


Patients with Crohn’s disease (CD) sometimes suffer from daily bouts of stomach pain and diarrhea. These constant gastrointestinal episodes can prevent them from absorbing enough nutrition to meet their needs, and, consequently, they can suffer from weakness, fatigue, and a general failure to flourish.

To treat Crohn’s disease, physicians use several different types of drugs. First there are the anti-inflammatory drugs, which include oral 5-aminosalicylates such as sulfasalazine (Azulfidine), which contains sulfur, and mesalamine (Asacol, Delzicol, Pentasa, Lialda, Apriso). These drugs, have several side effects, but on the whole are rather well tolerated. If these don’t work, then corticosteroids such as prednisone are used. These have a large number of side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity. More-serious side effects include high blood pressure, diabetes, osteoporosis, bone fractures, cataracts, glaucoma and increased chance of infection.

If these don’t work, then the stronger immune system suppressors are brought out. These drugs have some very serious side effects. Azathioprine (Imuran) and mercaptopurine (Purinethol) are two of the most widely used of this group. If used long-term, these drugs can make the patient more susceptible to certain infections and cancers including lymphoma and skin cancer. They may also cause nausea and vomiting. Infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia) are the next line of immune system suppressors. These drugs are TNF inhibitors that neutralize an immune system protein known as tumor necrosis factor (TNF). These drugs are also associated with certain cancers, including lymphoma and skin cancers. The next line of drugs include Methotrexate (Rheumatrex), which is usually used to treat cancer, psoriasis and rheumatoid arthritis, but methotrexate also quells the symptoms of Crohn’s disease in patients who don’t respond well to other medications. Short-term side effects include nausea, fatigue and diarrhea, and rarely, it can cause potentially life-threatening pneumonia. Long-term use can lead to bone marrow suppression, scarring of the liver and sometimes to cancer. You will need to be followed closely for side effects.

Then there are specialty medicines for patients who do not respond to other medicines or who suffer from openings in their lower large intestines to the outside world (fistulae). These include cyclosporine (Gengraf, Neoral, Sandimmune) and tacrolimus (Astagraf XL, Hecoria). These have the potential for serious side effects, such as kidney and liver damage, seizures, and fatal infections. These medications are definitely cannot be used for long period of time as their side effects are too dangerous.

If the patient still does not experience any relief, then two humanized mouse monoclonal antibodies natalizumab (Tysabri) and vedolizumab (Entyvio). Both of these drugs bind to and inhibit particular cell adhesion molecules called integrins, and in doing so prevent particular immune cells from binding to the cells in the intestinal lining. Natalizumab is associated with a rare but serious risk of a brain disease that usually leads to death or severe disability called progressive multifocal leukoencephalopathy. In fact, so serious are the side effects of this medicine that patients who take this drug must be enrolled in a special restricted distribution program. The other drug, vedolizumab, works in the same way as natalizumab but does not seem to cause this brain disease. Finally, a drug called Ustekinumab (Stelara) is usually used to treat psoriasis. Studies have shown it’s useful in treating Crohn’s disease and might useful when other medical treatments fail. Ustekinumab can increase the risk of contracting tuberculosis and an increased risk of certain types of cancer. Also there is a risk of posterior reversible encephalopathy syndrome. More common side effects include upper respiratory infection, headache, and tiredness.

If this litany of side effects sounds undesirable, then maybe a cell-based treatment can help Crohn’s patients. To that end, a clinical trial called the Autologous Stem Cell Transplantation International Crohn’s Disease or ASTIC trial was conducted and its results were published in the December 15th, 2015 edition of the Journal of the American Medical Association.

The ASTIC trial enrolled 45 Crohn’s disease patients, all of whom underwent stem cell mobilization with cyclophosphamide and filgrastim, and were then randomly assigned to immediate stem cell transplantation (at 1 month) or delayed transplantation (at 13 months; control group).  Blood samples were drawn and mobilized stem cells were isolated from the blood.  In twenty-three of these patients, their bone marrow was partially wiped out and reconstituted by means of transplantations with their own bone marrow stem cells. The other 22 patients were given standard Crohn disease treatment (corticosteroids and so on) as needed.

The bad news is that hematopoietic stem cell transplantations (HSCT) were not significantly better than conventional therapy at inducing sustained disease remission, if we define remission as the patient not needing any medical therapies (i.e. drugs) for at least 3 months and no clear evidence of active disease on endoscopy and GI imaging at one year after the start of the trial. All patients in this study had moderately to severely active Crohn’s disease that was resistant to treatment, had failed at least 3 immunosuppressive drugs, and whose disease that was not amenable to surgery.  All participants in this study had impaired function and quality of life.  Also, the stem cell transplantation procedure, because it involved partially wiping out the bone marrow, cause considerable toxicities.

Two patients who underwent HSCT (8.7%) experienced sustained disease remission compared to one control patient (4.5%). Fourteen patients undergoing HSCT (61%) compared to five control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months. Eight patients (34.8%) who had HSCTs compared to two (9.1%) patients treated with standard care regimens were free of the signs of active disease on endoscopy and radiology at final assessment.

However, there were 76 serious adverse events in patients undergoing HSCT compared to 38 in controls, and one patient undergoing HSCT died.

So increased toxicities and not really a clear benefit to it; those are the downsides of the ASCTIC study.  An earlier report of the ASTIC trial in 2013, while data was still being collected and analyzed was much more sanguine.  Christopher Hawkey, MD, from the University of Nottingham in the United Kingdom said this: “Some of the case reports are so dramatic that it’s reasonable to talk about this being a cure in those patients.”  These words came from a presentation given by Dr. Hawkey at Digestive Disease Week 2013.  Further analysis, however, apparently, failed to show a clear benefit to HSCT for the patients in this study.  It is entirely possible that some patients in this study did experience significant healing, but statistically, there was no clear difference between HSCT and conventional treatment for the patients in this study.

The silver lining in this study, however, is that compared to the control group, significantly more HSCT patients were able to stop taking all their immunosuppressive therapies for the three months prior to the primary endpoint. That is a potential upside to this study, but it is unlikely for most patients that this upside is worth the heightened risk of severe side effects. An additional potential upside to this trial is that patients who underwent HSCT showed greater absolute reduction of clinical and endoscopic disease activity. Again, it is doubtful if these potential benefits are worth the higher risks for most patients although it might be worth it for some patients.

Therefore, when HSCT was compared with conventional therapy, there was no statistically significant improvement in sustained disease remission at 1 year. Furthermore, HSCT was associated with significant toxicity. Overall, despite some potential upside to HSCT observed in this study, the authors, I think rightly, conclude that their data do not support the widespread use of HSCT for patients with refractory Crohn’s disease.

Could HSCT help some Crohn’s patients more than others? That is a very good question that will need far more work with defined patient populations to answer.  Perhaps further work will ferret out the benefits HSCT has for some Crohn’s disease patients relative to others.

The ASTIC trial was a collaborative project between the European Society for Blood and Marrow Transplantation (EBMT) and the European Crohn’s and Colitis Organization (ECCO) and was funded by the Broad Medical Foundation and the Nottingham Digestive Diseases Centers.

Sleep Deprivation Decreases Stem Cell Activity


We have all been there: You are at your computer, working hard and then a yawn hits you. Alternatively, you are on the phone late at night and you start to nod. We all have our late nights burning the midnight oil, but we need our shut-eye.

Now it turns out that sleep deprivation might wreak havoc with your stem cells. New research in mice might (let me emphasize, might) have profound implications for patients undergoing bone marrow stem cell transplants.

This research was led by Dr. Asya Rolls, who formerly worked as a postdoctoral research fellow at Stanford University, but is now an assistant professor at the Israel Institute of Technology.

With regards to the clinical implications of this work, Dr. Rolls said, “Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling. We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

Rolls and her colleagues used laboratory mice for this study and broke them into two different groups. One group of mice was physically handled by members of the research team for four hours in order prevent them from going to sleep. The other group of mice were not handled and slept soundly in their cages. Then Rolls and her collaborators isolated bone marrow stem cells from the sleepless and well-rested mice. These bone marrow stem cells were then used to them to help reconstitute the bone marrow of twelve different mice that had been given radiation treatments that wiped out their bone marrow stem cells. It is important to note that these donor mice had bone marrow stem cells that glowed when put under a fluorescent light.

The irradiated mice were then examined eight and 16 weeks after they had received the bone marrow stem cell transplants. By taking blood samples, Roll and others measured the production of blood cells by the transplanted bone marrow stem cells. Mind you, the irradiated mice also received some of their own bone marrow stem cells in combination with the bone marrow stem cells from the donor mice. This was to help determine the percentage of blood cells made by the stem cells from the donor mice. Surveys of the blood cells of the irradiated mice showed that donated stem cells from the mouse donors that had a good night’s sleep gave rise to about 26 percent of the examined blood cells. However, bone marrow stem cells from sleepless donor mice only produced approximately 12 percent of the surveyed blood cells.

Next, the Stanford team investigated the ability of the transplanted stem cells to find their way to the bone marrow of the recipient mice, twelve hours after transplantation. When the bone marrow of the donor mice was subjected to fluorescent light, the 3.3 percent of the bone marrow stem cells were from the well-rested donor mice. However, the same experiment in those recipient mice that had received mice had received bone marrow stem cells from the sleep-deprived mice showed that only 1.7 percent of the stem cells in the bone came from the donor mice. Thus the bone marrow stem cells from those mice that had a good night’s sleep were twice as likely to find their way to the bone marrow of the recipient.

When hematopoietic stem cells from the donor mice were tested in culture, stem cells from the sleepless mice showed a weak response to chemical cues found in bone marrow that activate migration to the bone marrow. Conversely, hematopoietic stem cells from the well-rested mice responded much more robustly to these same chemical cues and migrated appropriately.

Think of it; not sleeping for only four hours can decrease the activity of transplanted bone marrow stem cells by up to half. Remember that bone marrow stem cells contain the coveted hematopoietic stem cell population that produces all the blood cells coursing through our bloodstream. When transplanted into recipient animals (or patients), these stem cells must actively find their way to the bone marrow, take up residence there, and begin to produce all the blood cells necessary for the life and health of the recipient. Therefore even a small reduction in the health or activity of hematopoietic stem cells could drastically affect the success of the bone marrow transplant procedure.

Are the effects of sleeplessness permanent? Not at all, at least in mice. Rolls and her team showed that the decrease in bone marrow stem cell activity could be reversed by allowing the sleep-deprived mice to sleep. In fact, in the hands of Rolls and her co-workers, even letting mice get only two hours of recovery sleep effectively restored the activity of their bone marrow stem cells to properly reconstitute the bone marrow of a recipient in a bone marrow transplant procedure.

“Everyone has these stem cells, and they continuously replenish our blood and immune system,” said Rolls. “We still don’t know how sleep deprivation affects us all, not just bone marrow donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Bone marrow transplants are used to treat patients with blood cancers, immune system disorders or others types of conditions. Each year, many thousands of bone marrow transplant procedures are performed. Therefore refining the bone marrow stem cell transplant procedure is essential to helping patients who need such a procedure.

This study was published in Nature Communications, with Asya Rolls as the lead author, who did her work in the laboratory of Irving Weissman, the director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine.

Clincal Trial Validates Stem Cell-Based Treatments of Sickle Cell Disease in Adults


Santosh Saraf and his colleagues at the University of Illinois have used a low-dose irradiation/alemtuzumab plus stem cell transplant procedure to cure patients of sickle-cell disease. 12 adult patients have been cured of sickle-cell disease by means of a stem cell transplantation from a healthy, tissue-matched donor.

This new procedure obviates the need for chemotherapy to prepare the patient to receive transplanted cells and offers the possibility of curing tens of thousands of adults from sickle-cell disease.

Sickle cell disease is an inherited disease that primarily affects African-Americans born in the United States. The genetic lesion occurs in the beta-globin gene that causes hemoglobin molecules to assemble into filaments under low-oxygen conditions. These hemoglobin filaments deform red blood cells and cause them to plug small capillaries in tissues, causing severe pain, strokes and even death.

Fortunately, a bone marrow transplant from a healthy donor can cure sickle-cell disease, but few adults undergo such a procedure because the chemotherapeutic agents that are given to destroy the patient’s bone marrow leaves from susceptible to diseases, unable to make their own blood cells, and very weak and sick.

Fortunately, a gentler procedure that only partially ablate the patient’s bone marrow was developed at the National Institutes of Health ()NIH) in Bethesda, Maryland. Transplant physicians there have treated 30 patients, with an 87% success rate.

In the Phase I/II clinical trial at the University of Illinois, 92% of the patients treated with this gentler procedure that was developed at the NIH.

Approximately 90% of the 450 patients who received stem cells transplants for sickle-cell disease have been children. However, chemotherapy has been considered too risky for adult patients who are often weakened far more than children by it.

Adult sickle-cell patients live an average of 50 years with a combinations of blood transfusions and pain medicines to manage the pain crisis. However, their quality of life can be quite low. Now, with this chemotherapy-free procedure, adults with sickle-cell disease can be cured of their disease within one month of their transplant. They can even go back to work or school and operate in a pain-free fashion.

In the new procedure, patients receive immunosuppressive drugs just before the transplant, with a very low dose of whole body radiation. Alemtuzumab (Campath, Lemtrada) is a monoclonal antibody that binds to the CD52 glycoprotein on the surfaces of lymphocytes and elicits their destruction, but not the hematopoietic stem cells that gives rise to them.  Next, donor cells from a healthy a tissue-matched sibling or donor are transfused into the patient. Stem cells from the donor home to the bone marrow and produce healthy, new blood cells in large quantities. Patients must continue to take immunosuppressive drugs for at least a year.

In the University of Illinois trial, 13 patients between the ages of 17-40 were given transplants from the blood of a healthy, tissue-matched sibling. Donors must be tested for human leukocyte antigen (HLA) markers on the surfaces of cells. Ten different HLA markers must match between the donor and the recipient for the transplant to have the best chance of evading rejection. Physicians have transplanted two patients with good HLA matches, to their donor, but had a different blood type than the donor. In many cases, the sickle cells cannot be found in the blood after the transplant.

In all 13 patients, the transplanted cells successfully engrafted into the bone marrow of the patients, but one patient failed to follow the post-transplant therapy regimen and reverted to the original sickle-cell condition.

One year after the transplantation, the 12 successfully transplanted patients had normal hemoglobin concentrations in their blood and better cardiopulmonary function. They also reported significantly less pain and improved health and vitality,

For of the patients were able to stop post-transplantation immunotherapy, without transplant rejection or other complications.

“Adults with sickle-cell disease can be cured with chemotherapy – the main barrier that has stood in the way for so long,” said Damiano Rondelli, Professor of Medicine and Director of the Stem Cell Transplantation Program at the University of Illinois. “Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications.”

These data were published in the journal Biology of Blood and Marrow Transplantation, 2015; DOI 10.1016/j.bbmt.2015.08.036.

Bone Marrow Pretreatment with Hypomethylating Agents Improves Progression-Free Survival in Leumemia Patients


When patients have certain types of leukemia, they can be cured if they receive a bone marrow transplant from a healthy donor. The immune cells from the donated bone marrow will then attack the cancer cells vigorously, and the leukemia will slip into remission.

Such a strategy is called an “allogeneic bone marrow transplant,” and it is an effective way to treat some types of leukemia. However, this technique is risky and it usually involves some patient-related mortality. The problem is getting the transplanted cells to survive.

A new study from the University of Texas MD Anderson Cancer Center in Houston, Texas has examined over eighty patients who have received allogeneic bone marrow grafts for chronic myelomonocytic leukemia (CMML). Stefan O. Ciurea and his colleagues have identified a new pre-treatment that seems to decrease the degree of tumor relapse.  Their study was published in the Biology of Blood and Bone Marrow Transplantation.

83 consecutive patients with some form of CMML received an allogeneic bone marrow transplants between April 1991 and December 2013 were examined in detail. They asked if pre-treatment of the bone marrow stem cells with chemicals called “hypomethylating agents” before transplant improved progression-free survival.

Seventy-eight patients received “induction treatment” before transplant, 37 received hypomethylating agents and 41 received cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03). However, the transplant-related mortality 1 year post-transplant did not significantly differ between these groups (27% and 30%, respectively; p=0.84). The lower relapse rate resulted in a significantly higher 3-year progression-free survival rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; p=0.04).

This study supports the use of hypomethylating agents before allogeneic stem cell transplantation for patients with CMML to achieve remission and improve progression-free survival of patients. Of course future studies are needed to confirm these findings, but they suggest that pretreating bone marrow stem cells with hypomethylating agents prior to transplanting them will beef the cells up and help them life longer to fight tumors.

Adding Cyclosporin to Bone Marrow Might Increase Stem Cell Numbers, Quality, and Engraftment Efficiency


In the bone marrow, we have an army of blood cell-making stem cells called hematopoietic stem cells (HSCs) that make all the blood cells that course through our blood vessels. These cells divide throughout our lifetimes, and they replacement themselves while they generate all the red and white cells found in our blood.

hematopoietic-stem-jpg

HSCs are also the cells that are harvested during bone marrow aspirations and biopsies. Transplantation of HSCs can save the lives of patients with blood cancers or other types of blood-or bone marrow-based diseased.

Harvesting and transplanting HSCs is, therefore, a very important clinical strategy for treating many different types of blood disorders and diseases. However, this crucial strategy is limited by the relative rarity of HSCs in isolated bone marrow. Additionally, the number and function of HSCs deteriorate both during their collection from the bone marrow (BM) and during their manipulation outside the body. Fortunately, the development of culture conditions that best mimic the environment these cells experience in bone marrow (the so-called “HSC niche environment”) may help to minimize this loss.

Scanning electron microscopy of stem cells (yellow / green) in a scaffold structure (blue) serving as a basis for the artificial bone marrow.
Scanning electron microscopy of stem cells (yellow / green) in a scaffold structure (blue) serving as a basis for the artificial bone marrow.

One of the most important variables for HSC viability is oxygen concentration, since various studies have shown that the oxygen concentrations found in ambient air seems to be damaging to HSCs, which normally are found in rather oxygen-poor reaches in bone marrow. Researchers from the laboratory of Hal Broxmeyer at the Indiana University School of Medicine have discovered that HSCs suffer from ‘‘extra-physiologic oxygen shock/stress (EPHOSS)” if they are harvested under ambient oxygen conditions. On top of that, treatment of the collected HSCs with the immunosuppressant drug cyclosporin A (CSA) can inhibit this stress, enhance the yield of collected HSCs, and increase their transplantation efficiency.

When Broxmeyer and his colleagues compared mouse BM that had been harvested under normal oxygen concentrations (21% O2) and low-oxygen concentrations (3% O2), they observed that the hypoxic (low-oxygen) treatment caused a 5-fold increase in the number of Long Term (LT) self-renewing HSCs, and a decrease in harmful reactive oxygen species (ROS) and mitochondrial activity. Broxmeyer and others also confirmed the positive effect of hypoxia on HSC collection from human cord blood. When mouse BM collected under different conditions were assayed by competitive transplantation, the “hypoxic HSCs” engrafted more efficiently in recipient mice. This increased engraftment was not due to enhanced homing or reduced cell death. Instead it seems that the stress response to non-physiological oxygen concentrations (EPHOSS) has a rapid and significant damaging effect in HSCs.

Broxmeyer decided to take this study one step further. In mitochondria (the powerhouse of the cell), increased expression of the mitochondrial permeability transition pore (MPTP) seems to be one of the key mechanism by which oxidative stress affects HSCs.

mitochondrial permeability transition pore
mitochondrial permeability transition pore

Induction of the MPTP leads to mitochondrial swelling and uncoupled energy production (which leads to the generation of reactive oxygen species, otherwise known as “free radicals). This leads to cell death apoptosis and necrosis, and intermittent MPTP activation may also decrease stem cell function in general without killing the cells. Broxmeyer and his coworkers came upon a rather ingenious idea to use the drug cyclosporin A (CSA) to antagonize MPTP induction, since CSA inhibits the associated CypD (cyclophilin) protein. When HSCs were collected under high-oxygen conditions in the presence of CSA, there was a 4-fold increase in the recovery of LT-HSCs and enhanced engraftment levels compared to HSCs harvested in high-oxygen conditions without CSA. This link was further strengthened by examining the HSCs of mice with a deletion of the CypD gene. In these mice, HSCs collected under high-oxygen conditions showed increased LT-HSC recovery and decreased LT-HSC ROS levels compared to wild-type mice.

Cyclophilin
Cyclophilin

How, harvesting and processing HSCs from bone marrow in a low-oxygen environment within a transplant clinic is generally not possible. However, given the observed advantages, the application of CSA may represent an easy and attractive alternative. The authors of this paper (which was published in the journal Cell) note that CSA is already used in the clinic as an immunosuppressant. Therefore, this technique could potentially be rapidly adapted into bone marrow harvesting techniques.

An additional thought is that studies that use other types of stem cells for transplantation might also need to consider the effects of EPHOSS and oxygen concentration while preparing their cells in other model systems.

See “Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock” from Cell by Stuart P. Atkinson

Genetically Engineered Stem Cells to Treat Osteoporosis in Mice


Osteoporosis is a nasty condition characterized by weak and brittle bones often leading to devastating bone fractures and other injuries. Unfortunately, millions of people worldwide have been diagnosed with osteoporosis.

Osteoporosis

Contrary to popular belief, out bones are dynamic organs that undergo constant remodeling consisting of bone resorption and renewal. However, once bone resorption rates outpace bone renewal, bone densities decrease, which puts bones at risk of fractures. Medical researchers are would like to find new ways to not only discourage bone resorption, but generate new bone material to replace demineralized bone. Ideally, therapies would rejuvenate bone growth so that it the bone reverts back to its original density levels.

Now a promising strategy to accomplish this goal is relies on stem cell therapy. A collaborative study by Xiao-Bing Zhang and his colleagues from Loma Linda University and Jerry L. Pettis from the Memorial VA Medical Center has built on their prior work with genetically modified hematopoietic stem cells (HSCs) that identified a growth factor that caused a 45% increase in bone strength in mouse models. This work was published in the journal Proceedings of the National Academy of Sciences, USA.

Zhang and his coworkers wanted to find a gene therapy that promotes bone growth while minimizing side effects. To that end, Zhang’s group focused on a growth factor called PGDFB or “platelet-derived growth factor, subunit B.” The properties of this growth factor make it a promising candidate, since it is already FDA approved for treating bone defects in the jaw and mouth.

platelet-derived growth factor, subunit B
platelet-derived growth factor, subunit B

First, Zhang and others isolated HSCs from the bone marrow of donor mice. HSCs were chosen because they can be given intravenously, after which they will home in to one of the major sites of bone loss (the endosteal bone surface). The isolated HSCs were then genetically engineered to overexpress the growth factor PGDFB. Experimental mice were then irradiated to wipe out their own HSCs, and then these same mice were transplanted with the modified HSCs.

After four weeks, the upper leg bones of the mice (femur) were tested. Zhang and his colleagues found that PGDFB promoted new trabecular bone formation, but because the PGDFB was expressed at high levels, it negatively affected bone mineral density. Zhang and others then used weaker promoters to optimize the dosage of PGDFB expression in the HSCs. They discovered that the phosphoglycerate kinase promoter (PGK) worked well to mitigate the amount of PGDFB that is expressed in cells. When these HSCs were transplanted into irradiated mice, they observed increases in trabecular bone volume, thickness, and number as well as increases in connectivity density. Additionally, cortical bone volume increased by 20-30% while cortical porosity was reduced by 40%. Importantly, the lower dosage of PGDFB resulted in no observed decreases in bone mineral density due to osteomalacia or hyperparathyroidism.

These treated femurs and a control sample underwent three-point mechanical testing to test the integrity of the new bone. The PGK-PGDFB-treated femur displayed a 45% increase in maximum load-to-failure in the midshaft of the femur and a 46% increase in stiffness, indicating quality bone formation. Thus the new bone that is deposited it also of high quality.

The next step in this work would like to determine why this combination of a PGK promotor and PDGFB worked so well. Zhang and others have discovered that PDGFB promotes bone marrow mesenchymal stem cell formation and angiogenesis, which are two important factors in bone growth. They also found that optimizing the dosage of PDGFB is quite important for promoting osteoblast (bone-forming) cell formation.

Finally Zhang’s group investigated how osteoclastogenesis, or the creation of cells that reabsorb bone (osteoclasts) is affected by PDGFB with a PGK promotor. The treated femurs also had an increase in biomarkers for osteoclasts. This increase in both osteoblasts and osteoclasts indicates that the treated bones undergo the normal bone rebuilding and remodeling cycle.

Overall, this research provides a compelling investigational pathway for future cell therapies to treat osteoporosis. Mouse models show a fast-acting technique that result in bone formation and increasing bone strength.

Supercharging Stem Cells for Organ Transplant Patients


A biomedical research team at the University of Adelaide has designed a novel protocol for culturing stem cells that drives the cells to grow faster and become therapeutically stronger. This research was recently published in the international journal, Stem Cells, and is expected to lead to new treatments for transplant patients.

Kisha Sivanathan , a PhD student at the University of Adelaide’s School of Medicine and the Renal Transplant Unit at the Royal Adelaide Hospital, spoke about this exciting breakthrough in stem cell research: “Adult mesenchymal stem cells, which can be obtained from many tissues in the body including bone marrow, are fascinating scientists around the world because of their therapeutic nature and ability to cultivate quickly. These stem cells have been used for the treatment of many inflammatory diseases but we are always looking for ways in which to increase stem cells’ potency,” said Ms. Sivanathan, who is the lead author on this study.

Ms. Sivanathan continued: “Our research group is the first in the world to look at the interaction between mesenchymal stem cells and IL-17, a powerful protein that naturally occurs in the body during times of severe inflammation (such as during transplant rejection). We discovered that when cultured mesenchymal stem cells are treated with IL-17 they grow twice as fast as the untreated stem cells and are more efficient at regulating the body’s immune response.”

Stem cell therapy continues to show very promising signs for transplant patients and according to Ms Sivanathan, the IL-17 treated stem cells could potentially be even more effective at preventing and treating inflammation in transplant recipients. The particular goal in this case is to treat patients who have received organ transplants; and even help control organ rejection in transplant patients.

“Current drugs (immunosuppressant drugs) used to help prevent a patient rejecting a transplant suppress the whole immune system and can cause severe side effects, like cancer. However, stem cell therapy (used in conjunction with immunosuppressant drugs) helps patients ‘accept’ transplants while repairing damaged tissue in the body, resulting in less side effects,” says Ms Sivanathan. “We are yet to undertake clinical trials on the IL-17 treated stem cells but we anticipate that because this treatment produces more potent stem cells, they will be more effective than the untreated stem cells,” she said.

Gene Therapy/Stem Cell Treatment Cures Boys of Severe Genetic Disease


British doctors have successfully cured youngsters suffering from a deadly inherited genetic disorder using ground-breaking stem cell-based treatments. This is the harbinger of a new era of medicine and genetic therapies.

The young patients who participated in this trial suffer from the most severe form of a rare blood condition call “Wiskott-Aldrich Syndrome.” The trial participants have now been free of the disease for four years.

Patients with Wiskott-Aldrich syndrome are usually male, and they have a deficient immune system that fails to fight off common infections that usually do not affect most people and a reduced ability to form blood clots. The numbers, and size of platelets in the blood, which are the cells responsible for initiating blood clots, are abnormal in individuals with Wiskott-Aldrich syndrome; they have very small platelets and few of them. This condition is called microthrombocytopenia. This platelet abnormality leads to easy bruising or episodes of prolonged bleeding following minor traumas. Additionally, many types of white blood cells are abnormal or nonfunctional, and this increases the risk of several immune and inflammatory disorders. Often patients with Wiskott-Aldrich syndrome develop eczema, which is an inflammatory skin disorder characterized by abnormal patches of red, irritated skin. Affected individuals also have an increased susceptibility to infection, and developing autoimmune disorders. They also have an increased chance of developing some types of cancer, such as cancer of the immune system cells (lymphoma).

Wiskott-Aldrich syndrome is inherited from the X chromosome, and therefore, the condition is much more common in males than in females. Having said that, Wiskott-Aldrich syndrome is still a rather rare condition, with an estimated incidence of 1 – 10 cases per million males worldwide.

Mutations in the WAS gene cause Wiskott-Aldrich syndrome. The WAS gene encodes the WASP protein, which is found in all blood cells, and relays signals from the surface of blood cells to the actin cytoskeleton inside the cell. The actin cytoskeleton is a network of fibrous proteins that compose the cell’s interior structural framework. WASP signaling triggers cell movement and attachment to other cells and tissues. In white blood cells, WASP signaling induces the actin cytoskeleton to establish the interactions between cells and the foreign invaders targeted by them. Mutations in the WAS gene cause a lack of any functional WASP protein, and loss of WASP signaling. Thus white blood cells are less able to respond to foreign invaders, which cause many of the immune problems related to Wiskott-Aldrich syndrome. Similarly, decreased WASP function impairs platelet development, leading to reduced size and early cell death.

In the Britain, Wiskott-Aldrich syndrome affects fewer than one hundred children in Britain, but Daniel Wheeler, 15, of Bristol is one of them. Wheeler was among seven children who participated in the new gene therapy trial at centers in London and Paris.

Daniel was diagnosed with Wiskott-Aldrich syndrome when he was two years old and needed frequent medical care to manage his symptoms which included severe eczema, asthma and inability to fight infections. David’s older brother died from complications associated with the disease. However, since undergoing gene therapy in 2011 Daniel has shown no symptoms and doctors believe he is effectively cured.

Daniel’s mother Sarah, 50, who works in real estate in Bristol said: “Since being around two, Daniel has been in an out of hospital, but now his skin has cleared up and so has his asthma. It means he can get on with his life now.”

Adrian Thrasher, Professor in Pediatric Immunology, at Great Ormond Street Hospital in London, where David’s treatment was carried out, said that it offered new hope for people suffering from incurable disease. “We are entering a new era where genetic treatments are entering mainstream medicine and offering hope to patients for whom conventional treatments don’t work well or are simply unavailable,” he said.

“The work shows that this method is successful in patients who, in the past would have very little chance of survival without a well match bone marrow donor.

“It also excitingly demonstrates the potential for treatment of a large number of other diseases for which existing therapies are either unsatisfactory or unavailable.”

In this trial, David’s bone marrow stem cells were isolated and subjected to gene therapy in the laboratory. The faulty WAS gene was replaced with a healthy copy of the gene. These genetically repaired stem cells were replaced in David’s bone marrow where they began producing healthy blood cells that were free from the disease. Because the healthy blood cells were more durable and lived longer than the diseases ones, they eventually overtook the diseased ones.

Seven children between the ages of eight months and 15 years were selected for the trial because a bone marrow match could not be found. Without bone marrow transplantation, patients usually do not survive their teenage years. All the children had eczema and associated recurrent infections and most experienced severe bleeding and autoimmune disease that, in one case, confined the child to a wheelchair.

The children went from spending an average of 25 days in the hospital to no days in the hospital in the two years after the treatment. Furthermore the child using the wheelchair was able to walk again.

Fulvio Mavilio, Chief Scientific Officer at Genethon, the biotech company which developed the treatment said: “It is the first time that a gene therapy based on genetically modified stem cells is tested in an international clinical trial that shows a reproducible and robust therapeutic effect in different centers and different countries.”

Stem Cell Transplants for SCID Children – Earlier is Better


Severe Combined Immune Deficiency or SCID hamstrings the immune system of newborn children and prevents their immune systems from fighting off any diseases. Children born with SCID must be isolated in a germ-free environment and are sometimes called “bubble children,” since they must go out in the open in space suits that purify their air. However, if children with this “bubble boy” disease have a bone marrow transplant, they can survive. When, however is the best time to give these children such a transplant?

A new study by a research group at the Harvard-affiliated Dana Farber/Boston Children’s Cancer and Blood Disorders Center has reviewed the last ten years of data on treating these young patients. According to the conclusions of this study, children with SCID have the best chance of survival if they undergo a bone marrow stem cell transplant as soon after birth as possible. Consequently, genetic screening of newborn babies for SCID should be expanded, since this disorder leaves affected infants so vulnerable to infection that most die within the first year of life if untreated.

This new research was published in the New England Journal of Medicine, and analyzed data on 240 SCID children who underwent transplants at 25 centers across North America between Jan. 1, 2000, and Dec. 31, 2009 (before the U.S. Department of Health and Human Services recommended newborn screening for SCID in 2010). Currently, 21 states and the District of Columbia, which are home to about two-thirds of all babies born in the United States, screen newborns for SCID. Another nine states are expected to implement newborn screening by the end of 2014.

“The best way to identify patients that early when there is no family history of SCID is through newborn screening,” said Sung-Yun Pai, first author on the study. “Survival is much, much better if infants undergo transplant before they turn 3½ months old and before they contract any SCID-related infections,” said Pai. “The best way to identify patients that early when there is no family history of SCID is through newborn screening.”

While patient age was one of the strongest factors determining the survival of SCID infants, this study also showed that the infection status at the time of transplant and the donor source had the strongest impact on transplant outcomes (i.e., five-year survival and successful immune system reconstitution).

Interestingly, the data used in this study also showed that even though SCID is relatively rare, SCID is twice as common as once thought. “Some children who succumbed to unexplained infections probably suffered from SCID,” Pai noted. SCID is estimated to occur in one of every 50,000 births, up from earlier estimates of one in 100,000.

“Time is not the ally of children with SCID,” said Luigi Notarangelo of Boston Children’s Hospital, who was one of the study’s senior authors. Notarangelo is among those who lobbied successfully to establish SCID newborn screening in Massachusetts in 2009. “Because they do not have a functional immune system, the longer the wait before a transplant, the greater the risk they will contract a potentially devastating infection.”

Children who underwent transplant before 3½ months of age had excellent survival, and this was regardless of donor source or infection status. Likewise, children who underwent transplant with stem cells from a tissue-matched sibling donor. Children outside that age group also had very good survival regardless of donor source, but only if the patient did not have an active infection at the time of transplant. The effect of the donor type and pre-transplant conditioning on survival rates was important only in actively infected patients.

Other findings from this study included:
• 74 percent of the 240 patients studied survived at least five years.
• Among patients who underwent transplant at younger than 3½ months, 94 percent survived.
• Virtually all (97 percent) of the patients who received stem cells from a matched sibling donor survived.
• At 50 percent, survival was lowest among patients who were older than 3½ months and had active infections at the time of transplant. Actively infected infants who did not have a matched sibling donor and who received immunosuppressive or chemotherapy before transplant had particularly poor survival rates (39-53 percent).
• Among patients who never had an infection, 90 percent survived, as did 82 percent of patients whose infection had resolved before transplant.

While survivors who received chemotherapy conditioning had stronger immune systems after transplant, it is still unknown if the drugs used to wipe out the patient’s immune systems before the bone marrow transplant pose a long-term risk when given to such young patients.

“This study accomplishes several things,” she said. “First, it creates a baseline with which to compare patient outcomes since the advent of newborn screening for SCID. Second, it provides guidance for clinicians regarding the use of chemotherapy conditioning before transplantation. Third, it highlights the relative impacts of infection status and patient age on transplant success.

“Lastly, it establishes the importance of early detection and transplantation, which points to the benefit of expanding newborn screening for SCID as broadly as possible.”

New Standard of Care for Umbilical Cord Blood Transplants


New research led by John Wagner, Jr., M.D., director of the Pediatric Blood and Marrow Transplantation program at the University of Minnesota and a researcher in the Masonic Cancer Center, University of Minnesota, has established a new standard of care for children who suffer from acute myeloid leukemia (AML).

In a recent paper in the New England Journal of Medicine, Wagner and his coworkers compared clinical outcomes in children who suffered from acute leukemia and myelodysplastic syndrome who received transplants of either one unit or two units of partially matched cord blood. This large study was conducted at multiple sites across the United States, between December 2006 and February 2012. Coordinating the study was the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in collaboration with the Pediatric Blood and Marrow Transplant Consortium and the Children’s Oncology Group.

Umbilical cord blood provides a wonderfully rich source of blood-forming stem cells, and has been demonstrated to benefit many diseases of the blood or bone marrow, as in the case of leukemia and myelodysplasia, or bone marrow failure syndromes, hemoglobinopathies, inherited immune deficiencies and certain metabolic diseases. For leukemia patients cord blood offers several advantages since there is no need for strict tissue-type matching (human leukocyte antigen or HLA matching) or for a prolonged search for a suitable donor.

Wagner and others discovered that the survival rates of children who received either one or two units of umbilical cord blood were about the same, but, overall, their recorded survival rates were better than those reported in prior published reports. These higher survival rates, therefore, represent a new standard of care for pediatric patients, for whom there is often an adequate single cord blood unit, and for adults for usually require double units, since a single unit with an adequate number of blood-forming stem cells simply may not exist at time.

“Based on promising early studies using two cord blood units in adults for whom one unit is often not sufficient, we designed this study in order to determine if the higher number of blood forming stem cells in two cord blood units might improve survival,” explained Wagner. “What we found, however, was that both treatment arms performed very well with similar rates of white blood cell recovery and survival.”

Children with blood cancers who receive transfusions of umbilical cord blood show quantifiable clinical benefits even though the blood may not match their own tissue types. The reason stems from the immaturity of cord blood stem cells and their ability to suppress rejection from the immune system. This is an important aspect of umbilical cord blood transplants, since patients who cannot find a matched unrelated donor also benefit from cord blood transplants. However, cord collection from the placenta after birth often results in a limited number of blood-forming stem cells, which decreases the potential benefits of cord blood. The “double UCB approach” was pioneered at the University of Minnesota as a strategy to overcome this inherent limitation in the use of umbilical cord blood.

Despite the similarities in survival rates between children who received one unit or two units of cord blood, some differences were noted. Children transplanted with a single cord unit had faster recovery rates for platelets and lower risks of Graft Versus Host Disease; a condition in which the transplanted donor blood immune cells attack the patient’s body, which causes several complications.

“This is helpful news for physicians considering the best treatment options for their patients,” said Joanne Kurtzberg, M.D., chief scientific officer of the Robertson Clinical and Translational Cell Therapy Program, director of the Pediatric Blood and Marrow Transplant Program, co-director of the Stem Cell Laboratory and director of the Carolinas Cord Blood Bank at Duke University Medical Center. “We found children who have a cord blood unit with an adequate number of cells do not benefit from receiving two units. This reduces the cost of a cord blood transplant for the majority of pediatric patients needing the procedure. However, for larger children without an adequately dosed single cord blood unit, using two units will provide access to a potentially life-saving transplant.”

“The involvement of multiple research partners was instrumental to the success of the study completion,” added Dennis Confer, M.D., chief medical officer for the National Marrow Donor Program® (NMDP)/Be The Match® and associate scientific director for CIBMTR. “This trial is a testament to the importance of the BMT CTN and the collaboration of partners like the Children’s Oncology Group.”

Mary Horowitz, M.D., M.S., chief scientific director of CIBMTR and professor of medicine at the Medical College of Wisconsin, concurred. “Because of this tremendous collaboration, we were able to expand the scale of this research to multiple transplant centers across the United States and Canada. And the results will undoubtedly improve clinical practice, and most importantly, patient outcomes.”

Interestingly, in this study, patients who received cord blood with significant HLA mismatches showed no detrimental effects on their outcomes. Future studies will examine a closer look at how the HLA match within the cord blood unit impacts outcomes for patients, particularly those within minority populations.

Patient’s Own Stem Cells Treat Rare Neurological Disorder


Stiff-Person syndrome is a rare neurological disease that, for all intents and purposes, looks like an autoimmune disease. It is characterized by muscular rigidity that tends to come and go. This rigidity occurs in the muscles of the trunks and limbs. Patients with Stiff-Person syndrome also have an enhanced sensitivity to stimuli such as noise, touch, and emotional distress, and various stimuli may cause the patient to experience painful muscle spasms that cause abnormal postures and stiffening. Stiff-Person syndrome or SPS is more common in women than in men and SPS patients often suffer from other autoimmune conditions in addition to SPS (for example, pernicious anemia, diabetes, vitiligo, and thyroiditis). Unfortunately, the precise cause of SPS is not known, but again, it looks like an autoimmune condition.

A research team at Ottawa Hospital Research Institute has made a breakthrough in the successful treatment of SPS using bone marrow stem cell transplants. The medical director at the Ottawa Hospital Research Institute, Dr. Harold L. Atkins, who is also a physician in the Blood and Bone Marrow Transplant Program at The Ottawa Hospital and an associate professor at the University of Ottawa has used bone marrow transplants to two female SPS patients into remission.

SPS can leave patients bedridden and in severe pain, but thanks to Atkins and his team, the progression of the disease in these women has ceased, allowing both women to regain their previous function and leaving them well enough to return to work and normal everyday activities.

Adkins and his group published this case study in JAMA Neurology, which is produced by the Journal of the American Medical Association. This is the first documented report that taking stem cells from a person’s own body can produce long-lasting remission of stiff person syndrome.

“We approach these cases very carefully and are always aware that there have just been a few patients treated and followed for a short time,” says Dr. Atkins. Atkins and his extracted bone marrow stem cells from each woman, and then used chemotherapy to eliminate their immune systems. Once their immune system were reliably eliminated, both women had their own stem cells returned to their bodies in order to reconstitute their immune systems. This procedure essentially gives the immune system a “do-over.”.

“By changing the immune system, one hopes to put the stiff person syndrome into remission,” adds Dr. Atkins. “Seeing these two patients return to their normal lives is really every physicians dream.”

This very procedure, which is known as an “autologous stem cell transfer” or ASCT has been used to successfully treat people who suffer from autoimmune diseases such as multiple sclerosis, scleroderma, and systemic lupus erythematosis. Atkins and his team used high-doses of chemotherapy and antibodies that specifically bind lymphocytes to rid the women’s bodies of their rogue immune cells before their immune systems were regenerated using their own stem cells. Adkins an his colleagues viewed this as a viable treatment option based strategies that had been used to treat other autoimmune diseases.

Patient 1 was diagnosed with stiff person syndrome in 2005 at age 48 after experiencing leg stiffness and several falls. After her treatment, her symptoms disappeared and she was fully mobile again six months after receiving the stem cell transplant procedure in 2009.

Patient 2 was diagnosed with stiff person syndrome in 2008 at age 30. She had stopped working and driving, and had moved back in with her parents before her stem cell transplant in 2011. Also, she has been able to return to her work and previous activities, and has not had any stiff person syndrome symptoms in more than a year.

“The results achieved by Dr. Atkins and his team through this innovative treatment show how research at The Ottawa Hospital can lead to life-changing and, even life-saving care,” says Dr. Duncan Stewart, Chief Executive Officer and Scientific Director of the Ottawa Hospital Research Institute. “Translating research into better care for patients is what we’re all about at the research institute.”

Umbilical Cord Blood and Bone Marrow Transplants in Myelodysplastic Syndrome


Myelodysplasia syndrome (MDS) killed my mother. Therefore, this paper caught my eye.

This paper describes a multicenter study from Argentina that examined children with MDS. MDS affects the blood cell-producing stem cells in the bone marrow so that these cells make immature red blood cells that do not properly carry oxygen to tissues. The rogue stem cells produce droves and droves of these immature cells that overpopulate the bone marrow and crowd out the normal bone marrow stem cells. Patients with MDS suffer shortness of breath, weakness and fatigue, mental lapses, and other symptoms of anemia.  They also must rely on blood transfusions in order to keep them alive. Bone marrow transplants or umbilical cord transplants can cure MDS patients.

In this study, Ana Basquiera, from the Hospital Privado Centro Médico de Córdoba, Argentina, and her colleagues evaluated the overall survival, disease-free survival (DFS), non-relapse mortality (NRM) and relapse incidence in MDS children who underwent bone marrow and umbilical cord transplants. These children received these transplants in six different clinical throughout Argentina. All in all, 54 transplants were conducted in 52 patients. The mean age of these patients was 9 years old (range: 2–19), and 35 of the patients were males.

Several different types of MDS were seen in these patients, but all of them were not treatable by other means. Because MDS often precedes leukemia, seven (13%) patients at the time of the transplant transformed to acute myeloid leukemia (AML) and the diagnosis of two other patients also worsened.

All patients had their own bone marrow wiped out by means of a “conditioning regimen.” These are drugs that destroy the bone marrow stem cells of the patient and leave them without the means of make their own red blood cells or immune cells. Patients must then receive high doses of antibiotics and anti-fungal drugs while their bone marrow is repopulated. As you can guess, this is a nasty, dangerous procedure.

Of these patients, 63% received bone marrow stem cells, 26% stem cells from peripheral blood, and 11% umbilical cord blood. Five-year disease-free survival and overall survival were 50% and 55% respectively; and for patients with juvenile myelomonocytic leukemia, 57% and 67% respectively.

Cumulative incidence of non-relapse mortality and relapse were 27% and 21% respectively. Statistical analyses of the data from these treatments showed that patients who had received umbilical cord blood (HR 4.07; P = 0.025) and were younger than nine years old tended to have a lower overall survival rate. Also, younger patients who experienced graft-versus-host disease (GVHD), in which the engrafted immune cells begin to attack the tissues of the patient, had a higher rate of non-relapse mortality (no real surprise there).

Thus, more than half of the patients achieved long-term overall survival. The mortality and relapse rates were rather high, however, and it is possible that less toxic conditioning regimens or more intensive prevention of GVHD could lead to better results in some children. Until such procedures are make available, such mortality rates will probably remain high, even though the procedure does potentially cure the patients of MDS.  Thus this remains a “high risk, big pay-off” procedure.

This was published in Pediatric Blood and Cancer.

A Home A Stem Cell Could Love


In our bodies, stem cell populations live in specific places that are specially designed to accommodate them known as “stem cell niches.” Stem cell niches host and maintain stem cell populations, but the dependence of particular stem cells on their niche varies. For example, in the fruit fly, Drosophila melanogaster, the germ line stem cell niche can drive stem cells that have already begun to differentiate to revert into undifferentiated stem cells (see Brawley C and Matunis E. Science 2004;304:1331–4 and Kai T and Spradling A. Nature 2004;428:564–9). However, hair follicle stem cells do not revert when they return to their niche even if this niche has been depleted of stem cells (see Hsu Y-C, Pasolli HA, Fuchs E. Cell 2011;144:92–105). Also, blood cell-making stem cells that normally live in bone marrow can leave their niche in the bone marrow without losing their stem cell properties (Cao Y-A, et al., Proc Natl Acad Sci USA 2004;101:221–6). Finally, neural stem cells can exist and even self-renew outside their niche (Conti L, et al., PLoS Biol 2005;3:e283).

In order to properly grow stem cells in culture and manipulate them for therapeutic purposes, scientists have attempted to recapitulate stem cell niches in culture but only with very limited success.

Nevertheless, trying to get stem cells that have been introduced into a patient’s to engraft or make the new body their home has required a better understanding of stem cell niches.

To that end, Professor Claudia Waskow and her colleagues at the Technische Universität Dresden in Germany have utilized a downright ingenious method to make a mouse that can support the transplantation of human blood stem cells. This is despite the species barrier and, these mice do not need to have their own resident stem cell population obliterated with radiation.

How did Waskow and others do this? They used a mutation of a receptor called the “Kit receptor” to facilitate the engraftment of human cells. “What is the Kit receptor,” you ask? The Kit receptor is a protein in the membranes of blood stem cells that binds a soluble protein called stem cell factor (SCF). Stem cell factor drives certain types of blood cells to grow, and also mediates stem cells survival, proliferation and differentiation. Activation of the Kit receptor can also cause blood stem cells to leave the bone marrow and move into the peripheral circulation.

The Kit Receptor - AKA CD117
The Kit Receptor – AKA CD117

In the mouse model system designed by Waskow and others, the human blood stem cells grow and even differentiate into all blood-specific cell types without any additional treatment, and this includes the cells of the innate immune system. This is a milestone discovery because such cells normally do not form properly in “humanized” mice, but in Waskow’s experiment, these immune cells were efficiently generated. Significantly, these transplanted stem cells can be maintained in the mouse over a longer period of time compared to previously existing mouse models.

“Our goal was to develop an optimal model for the transplantation and study of human blood stem cells,” says Claudia Waskow, who recently took office of the professorship for “animal models in hematopoiesis” at the medical faculty of the TU Dresden. Before, coming to TU Dresden, Dr. Waskow was a group leader at the DFG-Center for Regenerative Therapies Dresden where most of the study was conducted.

Waskow’s team used a naturally occurring mutation of the Kit receptor and introduced it into her laboratory mice that lacked a functional immune system. This circumvented the two major obstacles of blood stem cell transplantation: the rejection by the recipient’s immune system and absence of free niche space for the incoming donor stem cells in the recipient’s bone marrow. Typically, the animal or the patient is treated with radiation to deplete the bone marrow of resident stem cells. This step, known as conditioning, creates usable space in the bone marrow for the implanted stem cells to take up residence and set up shop. However, irradiation is toxic a whole host of different cell types, not just bone marrow stem cells, and, unfortunately, has several strong side effects.

This Kit mutation in the mouse modifies the stem cell niche of the recipient mouse so that the resident stem cells are easily displaced by the human donor stem cells that possess a functional Kit receptor. This replacement works so well that irradiation was unnecessary, which allowed the study of human blood development in a physiological setting.

Waskow would like to use this new model system to study diseases of the human blood and immune system or to test new treatment options.

These data show that the Kit receptor (also known as CD117) is important for the function of human blood stem cells in a transplantation setting. Further work will concentrate on applying this new knowledge about the role of the receptor to improve conditioning therapy in bone marrow transplantation patients.

Expanding Functional Cord Blood Stem Cells for Transplantation


Patients who suffer from blood-based diseases such as leukemia, lymphoma, and other blood-related diseases sometimes require bone marrow transplants in order to live. The paucity of available bone marrow necessitates the use of umbilical cord blood for these patients, but cord blood suffers from one flaw and that is small volumes of blood and low numbers of stem cells. Scientists have tried to grow cord blood stem cells in culture in order to beef up the numbers of stem cells, but cord blood stem cells sometimes lose their ability to repopulate the bone marrow while in culture.

To solve this problem, researchers at the Icahn School of Medicine at Mount Sinai have designed a new technique to expand the number of cord blood stem cells without causing any loss of potency.

“Cord blood stem cells have always posed limitations for adult patients because of the small number of stem cells present in a single collection,” said Partita Chaurasia of the Tisch Cancer Institute at Mount Sinai. “These limitations have resulted in a high rate of graft failure and delayed engraftment in adult patients.”.

Chaurasia and coworkers used a technique called “epigenetic reprogramming” to reshape the structure of the genome of the stem cells. They used a combination of a drug called valproic acid and histone deacetylase inhibitors (HDACIs). The valproic acid-treated cells produced greater numbers of marrow repopulating stem cells in culture. These expanded cord blood stem cells were also able to reconstitute the bone marrow of immune-deficient mice, and when the reconstituted bone marrow of that mouse could be used to reconstitute the bone marrow of another immune-deficient mouse. Bone marrow from this second mouse could also reconstitute the bone marrow of a third immune deficient mouse.

These results have extremely important implications for patients who are in the midst of a battle with blood cancers, and might mean the difference between a successful cord blood transplant and one that fails.