The Founder Cell Identity Does Not Affect iPS Cell Differentiation to Hematopoietic Stem Cell Fate


Induced pluripotent stem cells (iPSCs) have many of the characteristics of embryonic stem cells, but are made from mature cells by means of a process called cell reprogramming. To reprogram cells, particular genes are delivered into mature cells, which are then cultured until they h:ave the growth properties of pluripotent cells. Further tests are required to demonstrate that the growing cells actually are iPSCs, but once they pass these tests, these cells can be grown in culture indefinitely and, ideally, differentiated into just about any cell type in our bodies (caveat: some iPSC lines can only differentiate into particular cell lineages). Theoretically, any cell type can be reprogrammed into iPSCs, but work from many laboratories has demonstrated that the identity of the founder cell influences the type of cell into which it can be reprogrammed.

Founder cells can be easily acquired from a donor and come in one of four types: fibroblasts (in skin), keratinocytes (also from skin), peripheral and umbilical cord blood, and dental pulp cells (from baby teeth). A variety of laboratories from around the world have made iPSC lines from a gaggle of different founder cells. Because of the significant influence of founder cells for iPSC characteristics, the use of iPSCs for regenerative medicine and other medical applications requires that the desired iPSC line should be selected based on the founder cell type and the characteristics of the iPSC line.

However, the founder cell identity is not the only factor that affects the characteristics of derived iPSC lines. The methods by which the founder cells are reprogrammed can also profoundly contribute to the differentiation efficiency of iPSC lines. According to Yoshinori Yoshida, Associate Professor at the Center for iPSC Research and Application (CiRA) at Kyoto University, the most commonly used methods of cell reprogramming utilize retroviruses, episomal/plasmids, and Sendai viruses to move genes into cells.

The cells found in blood represent a diverse group of cells that includes red blood cells that carry oxygen, platelets that heal wounds, and white blood cells that fight off infection. All the cells in blood are made by bone marrow-specific stem cells called “hematopoietic stem cells.” The production of clinical grade blood has remained a kind of “holy grail” for cellular reprogramming studies. Some scientists have argued that in order to make good-quality hematopoietic cells, the best founder cells are hematopoietic cells. Is this true? Yoshida and his colleagues examined a very large number of iPSC lines that were made from different founder cells and with differing reprogramming methods.  The results of these experiments were published in the journal Cell Stem Cell (doi:10.1016/j.stem.2016.06.019).

Remarkably, Yoshida and his crew discovered that neither of these factors has a significant effect. What did have a significant effect were the expression of certain genes and the position of particular DNA methylations. These two factors were better indicators of the efficiency at which an iPSC line could differentiate into the hematopoietic stem cells.

“We found the IGF2 (Insulin-like Growth Factor-2) gene marks the beginning of reprogramming to hematopoietic cells”, said Dr. Masatoshi Nishizawa, a hematologist who works in Yoshida’s lab and is the first author of this new study. Higher expression of the IGF2 gene is indicative of iPSCs initiating differentiation into hematopoietic cells. Even though IGF2 itself is not directly related to hematopoiesis, its uptake corresponded to an increase in the expression of those genes involved in directing differentiation into hematopoietic stem cells.

Although IGF2 marked the beginnings of differentiation to hematopoietic lineage, the completion of differentiation was marked by the methylation profiles of the iPS cell DNA. “DNA methylation has an effect on a cell staying pluripotent or differentiating,” explained Yoshida. Completion of the final stages of differentiation was highly correlated with less aberrant methylation during the reprogramming process. Blood founder cells showed a much lesser tendency to display aberrant DNA methylation patterns than did other iPSC lines made from other founder cells. This probably explains why past experiments seemed to indicate that the founder cell contributes to the effectiveness of differentiating iPS cells to the hematopoietic stem cell lineage.

These findings reveal molecular factors that can be used to evaluate the differentiation potential of different iPSC lines, which should, hopefully, expedite the progression of iPSCs to clinical use. Nishizawa expects this work to provide the basis for evaluating iPSC lines for the preparation of other cell types. “I think each cell type will have its own special patterns,” he said.

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.

Musashi-2 Protein Increases Number Hematopoietic Stem Cells in Umbilical Cord Blood


Umbilical cord blood infusions save the lives of many children and adults each year. Umbilical cord blood contains hematopoietic stem cells (HSCs) that can replace those lost to anticancer treatments, chemicals, or bone marrow collapse. However, despite their advantages for transplantation, the clinical use of umbilical cord blood is limited by the fact that HSCs in cord blood are found only in small numbers.

Small molecules that enhance hematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified (see Boitano, A. E. et al. Science 329, 1345–1348 (2010), and Fares, I. et al. Science 345, 1509–1512 (2014). Unfortunately, the mechanisms of action or the nature of the pathways they impinge on are poorly understood.

Now a research team from McMaster University’s Stem Cell and Cancer Research Institute have discovered a key protein in the HSC/HSPC regenerative signaling pathway.

Kristin J. Hope and her team have elucidated the role of a protein called Musashi-2 in the function and development of HSCs.

Dr. Hope says that this discovery could help the tens of thousands of patients who suffer from blood-based disorders, including leukemia, lymphoma, aplastic anemia, sickle-cell disease, and more.

“We’ve really shone a light on the way these stem cells work,” she said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control over the regeneration of these cells, more people will be able to get the treatment they need.”

Only about five percent of all umbilical cord blood samples contain enough HSCs for a transplant, which is unfortunate because umbilical cord blood is less likely to be rejected by the immune system, because of the immaturity of the cells, and is also rather abundant.

Growing HSCs in culture is a possibility, but this remains a somewhat poorly understood and ill-defined procedure.

Musashi-2 is an RNA-binding protein in cells and was actually named for the Japanese samurai who fought using two swords.

In collaboration with researchers in Dr. Gene Yeo’s lab at the University of California San Diego, Dr. Hope’s lab has found that the Musashi-2 protein plays a pivotal role in controlling stem cell production in human cord blood HSCs. When Musashi-2 levels in HSCs are the knocked down, the cod blood HSCs were no longer able to regenerate the blood system. Conversely, when the levels of Musashi-2 were increased, the number of HSCs in the cord blood sample increased significantly.

The Hope’s group new discovery has identified a new way to tightly control on the development of HSCs. Essentially, Hope and her colleagues have discovered a new way to make more cord blood stem cells in a dish.

In the past, attempts to control HSC function and development has been approached at the level of transcriptional factors. The Hope lab’s approach of directing stem cell function through manipulation of an RNA-binding protein is somewhat novel, and represents a paradigm shift in the way we think about stem cell biology.

“This discovery really highlights the underappreciated role that RNA-binding protein-mediated control has on the properties of stemness in the blood system,” explained Dr. Hope.

This paradigm shift provides new targets for pharmaceuticals that may be able to expand these cells in a safe and targeted manner.

These findings represent an important step forward in surmounting the obstacles associated with stem cell transplants. According to Dr. Hope, the ability to increase the number of available cord blood stem cells has the potential to “mitigate a lot of the problems that arise post-transplantation.” Elaborating further, Dr. Hope explained that stem cells from cord blood are a “safer and more efficient transplant product,” and detailed how their use could reduce the number of patient follow-up visits and treatments required post-transplantation. Streamlining the transplantation process could help to alleviate the stress on the healthcare system and open up space for more transplant patients.

SEPCELL Trial Tests Fat-Derived Stem Cells as a Treatment for Sepsis


The Belgium-based biotechnology company, TiGenix, has launched a clinical trial entitled SEPCELL that uses fat-derived stem cells (called Cx611) to treat severe sepsis secondary to acquired pneumonia (also known as sCAP). SEPCELL is a randomized, double-blind, placebo-controlled, Phase 1b/2a study of sCAP patients who require mechanical ventilation and/or vasopressors.

SEPCELL will, hopefully, enroll 180 patients and will be conducted at approximately 50 centers throughout Europe. Subjects who participate in this trial will be randomly assigned to receive either an investigational product or placebo on days 1 and 3. All patients will be treated with standard care, which usually includes broad-spectrum antibiotics and anti-inflammatory drugs.

The primary endpoint of this clinical trial will examine the number, frequency, and type of adverse reactions during the 90-day period of the trial. The secondary endpoints of the SEPCELL trial include reduction in the duration of mechanical ventilation and/or vasopressors, overall survival, clinical cure of sCAP, and other infection-related endpoints. SEPCELL will also assess the safety and efficacy of the expanded allogeneic adipose stem cells (eASCs) that will be intravenously delivered to some of the patients in this study.

The SEPCELL trial will be managed by TFS International, a company based in Lund, Sweden. TFS has extensive experience in running sepsis trials and hospital-based trials.

Sepsis is a potentially life-threatening complication of infection that occurs when inflammatory molecules (cytokines and chemokines) released into the bloodstream to fight the infection trigger systemic inflammation.  This body-wide inflammation has the ability to trigger a cascade of detrimental changes that damage multiple organ systems and cause them to fail. If sepsis progresses to “septic shock,” blood pressure drops dramatically, which may lead to death. Patients with “severe sepsis” require close monitoring and treatment in a hospital intensive care unit. Drug therapy is likely to include broad-spectrum antibiotics, corticosteroids, vasopressor drugs to increase blood pressure, as well as oxygen and large amounts of intravenous fluids. Supportive therapy may be needed to stabilize breathing and heart function and to replace kidney function. Patients with severe sepsis have a low survival rate so there is a critical need to improve the effectiveness of current therapy. Only a small number of new molecular entities are currently in development for severe sepsis.

Severe sepsis and septic shock significantly affect public health and these event also are leading causes of mortality in intensive care units.

Severe sepsis and septic shock have an incidence of about 3 cases per 1,000, but due to the aging of the population and an increase in drug resistant bacteria.

Cx611 is an intravenously-administered concoction that consists of allogeneic eASCs. These cells are largely mesenchymal stem cells that secrete an impressive array of molecules that suppress the type of immune responses that damage organs during events like septic shock.  eASCs have a higher proliferation rate in culture and faster attachment than bone marrow-based mesenchymal stem cells in cell culture.  ASCs are also less prone to senescence and differentiation.  Their differentiation capacity decreases with expansion time without losing immunomodulatory properties.  These eASCs also have superior inflammation targeting capacities than bone marrow-based mesenchymal stem cells, and are safe, since they do not express ligands for receptors on Natural Killer cells that, and therefore, are unlikely to elicit an immune rejection.

In May 2015, TiGenix completed a Phase 1 sepsis challenge that demonstrated that Cx611 is safe and well tolerated. That trial began in December 2014, and was a placebo-controlled dose-ranging study (3 doses of eASC’s) in which 32 healthy male volunteers were randomized to receive Cx611 or placebo in a ratio of 3:1. Primary endpoints were vital signs and symptoms, laboratory measures and functional assays of innate immunity. All 32 volunteer subjects were recruited and dosed by March 2015. By May, 2015, the phase I trial data essentially demonstrated the safety and tolerability of Cx611.  On the strength of that phase I trial, TiGenix designed a Phase 1b/2a trial in severe sepsis secondary to sCAP in which they expecet to enroll 180 subjects across Europe.

SEPCELL was funded by a €5.4 million grant ($6.14 million) from the European Union.

Hematopoietic Stem Cells Use a Simple Heirarchy


New papers in Science magazine and the journal Cell have addressed a long-standing question of how the descendants of hematopoietic stem cells in bone marrow make the various types of blood cells that course through our blood vessels and occupy our lymph nodes and lymphatic vessels.

Hematopoietic stem cells (HSCs) are partly dormant cells that self-renew and produce so-called “multipotent progenitors” or MPPs that have reduced ability to self-renew, but can differentiate into different blood cell lineages.

The classical model of how they do this goes like this: the MPPs lose their multipotency in a step-wise fashion, producing first, common myeloid progenitors (CMPs) that can form all the red and white blood cells except lymphocytes, or common lymphoid progenitors (CLPs) that can form lymphocytes (see the figure below as a reference). Once these MPPs form CMPs, for example, the CMP then forms either an MEP that can form either platelets or red blood cells, or a GMP. which can form either granulocytes or macrophages. The possibilities of the types of cells the CMP can form in whittled down in a step-by-step manner, until there is only one choice left. With each differentiation step, the cell loses its capacity to divide, until it becomes terminally differentiated and becomes platelet-forming megakarocyte, red blood cell, neutrophil, macrophage, dendritic cells, and so on.

hematopoiesis-from-multipotent-stem-cell

These papers challenge this model by arguing that the CMP does not exist. Let me say that again – the CMP, a cell that has been identified several times in mouse and human bone marrow isolates, does not exist. When CMPs were identified from mouse and human none marrow extracts, they were isolated by means of flow cytometry, which is a very powerful technique, but relies on the assumption that the cell type you want to isolate is represented by the cell surface protein you have chosen to use for its isolation. Once the presumptive CMP was isolated, it could recapitulate the myeloid lineage when implanted into the bone marrow of laboratory animals and it could also produce all the myeloid cells in cell culture. Sounds convincing doesn’t it?

In a paper in Science magazine, Faiyaz Notta and colleagues from the University of Toronto beg to differ. By using a battery of antibodies to particular cell surface molecules, Notta and others identified 11 different cell types from umbilical cord blood, bone marrow, and human fetal liver that isolates that would have traditionally been called the CMP. It turns out that the original CMP isolate was a highly heterogeneous mixture of different cell types that were all descended from the HSC, but had different developmental potencies.

Notta and others used single-cell culture assays to determine what kinds of cells these different cell types would make. Almost 3000 single-cell cultures later, it was clear that the majority of the cultured cells were unipotent (could differentiate into only one cell type) rather than multipotent. In fact, the cell that makes platelets, the megakarocyte, seems to derive directly from the MPP, which jives with the identification of megakarocyte progenitors within the HSC compartment of bone marrow that make platelets “speedy quick” in response to stress (see R. Yamamoto et al., Cell 154, 1112 (2013); S. Haas, Cell Stem Cell 17, 422 (2015)).

Another paper in the journal Cell by Paul and others from the Weizmann Institute of Science, Rehovot, Israel examined over 2700 mouse CMPs and subjected these cells to gene expression analyses (so-called single-cell transriptome analysis). If the CMP is truly multipotent, then you would expect it to express genes associated with lots of different lineages, but that is not what Paul and others found. Instead, their examination of 3461 genes revealed 19 different progenitor subpopulations, and each of these was primed toward one of the seven myeloid cell fates. Once again, the presumptive CMPs looked very unipotent at the level of gene expression.

One particular subpopulation of cells had all the trappings of becoming a red blood cell and there was no indication that these cells expressed any of the megakarocyte-specific genes you would expect to find if MEPS truly existed. Once again, it looks as though unipotency is the main rule once the MPP commits to a particular cell lineage.

Thus, it looks as though either the CMP is a very short-lived state or that it does not exist in mouse and human bone marrow. Paul and others did show that cells that could differentiate into more than one cell type can appear when regulation is perturbed, which suggests that under pathological conditions, this system has a degree of plasticity that allows the body to compensate for losses of particular cell lineages.

A model of the changes in human My-Er-Mk differentiation that occur across developmental time points. Graphical depiction of My-Er-Mk cell differentiation that encompasses the predominant lineage potential of progenitor subsets; the standard model is shown for comparison. The redefined model proposes a developmental shift in the progenitor cell architecture from the fetus, where many stem and progenitor cell types are multipotent, to the adult, where the stem cell compartment is multipotent but the progenitors are unipotent. The grayed planes represent theoretical tiers of differentiation.
A model of the changes in human My-Er-Mk differentiation that occur across developmental time points.
Graphical depiction of My-Er-Mk cell differentiation that encompasses the predominant lineage potential of progenitor subsets; the standard model is shown for comparison. The redefined model proposes a developmental shift in the progenitor cell architecture from the fetus, where many stem and progenitor cell types are multipotent, to the adult, where the stem cell compartment is multipotent but the progenitors are unipotent. The grayed planes represent theoretical tiers of differentiation.

Fetal HSCs, however, are a bird of a different feather, since they divide quickly and reside in fetal liver.  Also, these HSCs seem to produce CMPs, which is more in line with the classical model.  Does the environmental difference or fetal liver and bone marrow make the difference?  In adult bone marrow, some HSCs nestle next to blood vessels where they encounter cells that hang around blood vessels known as “pericytes.”  These pericytes sport a host of cell surface molecules that affect the proliferative status of HSCs (e.g., nestin, NG2).  What about fetal liver?  That’s not so clear – until now.

In the same issue of Science magazine, Khan and others from the Albert Einstein College of Medicine in the Bronx, New York, report that fetal liver also has pericytes that express the same cell surface molecules as the ones in bone marrow, and the removal of these cells reduces the numbers of and proliferative status of fetal liver HSCs.

Now we have a conundrum, because the same cells in bone marrow do not drive HSC proliferation, but instead drive HSC quiescence.  What gives? Khan and others showed that the fetal liver pericytes are part of an expanding and constantly remodeling blood system in the liver and this growing, dynamic environment fosters a proliferative behavior in the fetal HSCs.

When umbilical inlet is closed at birth, the liver pericytes stop expressing Nestin and NG2, which drives the HSCs from the fetal liver to the other place were such molecules are found in abundance – the bone marrow.

These models give us a better view of the inner workings of HSC differentiation.  Since HSC transplantation is one of the mainstays of leukemia and lymphoma treatment, understanding HSC biology more perfectly will certainly yield clinical pay dirt in the future.

 

Fat-Based Stem Cell Product HemaXellerate Will be Tested in Clinical Trials for Aplastic Anemia


A regenerative medicine company called Regen BioPharma, Inc., has announced that it received a communication from the U.S. Food and Drug Administration that grants it permission to initiate clinical trials under its Investigational New Drug (IND) #15376.

Granting of the IND gives the green light to Regen BioPharma to begin testing their product HemaXellerate in clinical trials with human patients. HemaXellerate is a personalized stem cell treatment for patients whose bone marrow no longer works (aplastic anemia). It uses fat-based stem cells from a patient’s own belly fat to treat bone marrow that has been damaged. HemaXellerate uses the patient’s own fat-based stem cells as a source of endothelial (blood vessel) cells to heal damaged bone marrow.

Aplastic anemia occurs when the bone marrow stops producing sufficient numbers of blood cells. It is a potentially fatal disease of the bone marrow that leads to bleeding, infection and fever. Patients with severe or even very severe aplastic anemia have a mortality rate of greater than 70%. Current treatments for aplastic anemia include blood transfusions, immunosuppression and stem cell transplantation.

This Phase I clinical trial will treat patients who have been diagnosed with refractory aplastic anemia, which includes those patients with aplastic anemia who were unsuccessfully treated with first-line immunosuppressive therapy. Patients treated with HemaXellerate with be followed for safety parameters and signals of treatment efficacy. Since this will be an unblinded trial, all data will be available as the study progresses.

“Current drug-based approaches for healing bone marrow dysfunction involve flooding the body with growth factors, which is extremely expensive and causes unintended consequences because of lack of selectivity,” said Harry Lander, Ph.D., President and Chief Scientific Officer of Regen Biopharma. “By utilizing a cell-based approach that both modulates the immune system and stimulates production of blood cells, we aim to offer alternatives to the current approaches to treating patients with aplastic anemia. This product will complement our immune-modulatory pipeline that includes a potential novel checkpoint inhibitor.”

If HemaXellerate passes this clinical trial, Regen Biopharma would like to position HemaXellerate as a treatment for bone marrow dysfunction on par with other members of the hematopoietic growth factor market that includes drugs such as Neupogen®, Neulasta®, Leukine® and Revolade®.

“The FDA clearance marks a substantial step for Regen, in that we are now a clinical-stage company. We are grateful to our collaborators and scientific advisory board members who have worked tirelessly in bringing our product to the point where the FDA has permitted treatment of patients,” said David Koos, Ph.D., Chairman and Chief Executive Officer of Regen BioPharma. “We believe the success of today will not only allow for the rapid execution of HemaXellerate’s development plan, but will also allow for more rapid translation of the company’s other immune modulatory products to the clinic.”