Stanford study finds Induced pluripotent stem cells match embryonic stem cells in modeling human disease

Investigators from Stanford University School of Medicine have shown that induced Pluripotent Stem cells (iPSCs), which are made from adult cells through genetic engineering techniques, are a possible alternative to human embryonic stem cells when it comes to modeling those defects caused by a particular genetic condition. The example used in this study was Marfan syndrome, and in this study, iPSCs modeled the disease as well as embryonic stem cells (ESCs). Thus, iPSCs could be used to examine the molecular aspects of Marfan on a personalized basis. Embryonic stem cells, on the other hand, can’t do this because their genetic contents are those of the donated embryo are not the same as the patient’s.

Marfan syndrome is an inherited connective-tissue disorder that occurs in one in 10,000 to one in 20,000 individuals. It results from a large number of defects in one gene called “fibrillarin.” People with Marfan syndrome tend to be very tall and thin, and also tend to suffer from osteopenia, or poor bone mineralization. Medical experts have speculated that Abraham Lincoln, for example, suffered from this disorder. Marfan can also profoundly affect the eyes and cardiovascular system.

This proof-of-principle study, with regards to the utility of iPSCs also has more universal significance; it advances the credibility of using iPSCs to model a broad range of human diseases. iPSCs, unlike ESCs, are easily obtained from virtually anyone and possess a genetic background identical to the patient from which they were derived. Moreover, they carry none of the ethical controversy associated with the necessity of destroying embryos.

“Our in vitro findings strongly point to the underlying mechanisms that may explain the clinical manifestations of Marfan syndrome,” said Michael Longaker, MD, professor of surgery and senior author of the study, which will be published online Dec. 12 in Proceedings of the National Academy of Sciences. Longaker is the Dean P. and Louise Mitchell Professor in the School of Medicine and co-director of the school’s Institute for Stem Cell Biology and Regenerative Medicine. The study’s first author is Natalina Quarto, PhD, a senior research scientist in Longaker’s laboratory.

In this study, both iPSCs and ESCs, and embryonic stem cells that carried a mutation that causes Marfan syndrome showed impaired ability to form bone, and all too readily formed cartilage. These aberrations mirror the most prominent clinical manifestation of the disease.

iPSCs were discovered in 2006, and are derived from fully differentiated tissues such as the skin. However, they harbor the same capacity as embryonic stem cells; namely to differentiate into all the tissues of the body, and replicate for indefinite periods in a cell culture dish. Because iPSCs offer an ethically uncomplicated alternative to ESCs, IPSCs have fueled the hope that they can replace ESCs in scientists’ efforts to analyze, in a dish, those cellular defects ultimately responsible for diseases ranging from diabetes to Parkinson’s and even such complex conditions as cardiovascular disease and autism.

One hope for iPSCs is to be able to differentiate them in a dish into tissues of interest and then study these cells and their characteristics. This would help scientists better understand diseases in a patient-specific way, which would be impossible to do with ESCs unless ESCs were made from donated human eggs that were modified by cloning procedures. Cloning human embryos to the blastocyst stage has yet to occur, which makes this option technically impossible at the present time.

While scientists want to us iPSCs to develop therapeutic applications for regenerative medicine. This strategy, however, is technically more difficult, since scientists will have to develop the capacity first to repair genetic defects within cells before they can be used for regenerative medicine. iPSCs in theory might be a better bet because they are derived from patients’ own cells and, therefore, are less likely to provoke graft rejection than similar tissues produced using a donor embryo’s ESCs.

Unfortunately, several studies have reported subtle differences between iPSCs and ESCs, and these differences imply that the two cell types may not be equivalent. Stem cell experts have wondered whether these differences may render iPSCs inadequate substitutes for ESCs in modeling disease states, but this Stanford study suggests otherwise.

Geron Corporation Announces Phase II Trial for Brain-Specific Anticancer Drug GNR1005

After a successful completion of a Phase I study, Geron Corporation announces the initiation of a phase II trial for its GRN1005 anticancer drug. This drug was designed to specifically treat tumors that have metastasized (spread) to the brain from the lung. This clinical trial is called GRABM-L, which stands for GRN1005 Against Brain Metastases – Lung cancer). This phase II trial is designed to determine the efficacy of GRN1005 in patients with brain metastases arising from non-small cell lung cancer (NSCLC).

GRN1005 is a novel cancer drug that consists of three molecules of the anticancer drug paclitaxel linked to a 19 amino acid peptide (Angiopep-2). This 19-amino acid peptide binds to a receptor called the “lipoprotein receptor-related protein 1” (LRP1), which is one of the most highly expressed receptors on the surface of the blood-brain barrier (BBB). Brain tumor treatment is exceedingly difficult because the central nervous system is surrounded by the BBB. The BBB prevents molecules from entering the brain unless they can bind specific receptors. When GRN1005 binds to the LRP1 receptor, the binding facilitates “receptor-mediated transport,” or transcytosis, across the BBB into the brain tissue. Conveniently, LRP1 is also very heavily expressed in many tumors. Therefore, once GRN1005 enters the brain, it can gain entry into tumor cells. GRN1005 is a “prodrug,” which means that the form that the patient takes is inactive, but the drug becomes active once it enters cells and is cleaved by enzymes called “esterases” to release active paclitaxel from the peptide.

Geron’s Executive Vice President, Head of R&D and Chief Medical Officer, Stephen M. Kelsey, M.D., said: “With the treatment of the first patient in the GRABM-L study, we have initiated both of the planned Phase 2 clinical trials of GRN1005 in patients with cancer metastases in the brain, a significant unmet medical need for which there are currently no approved drug therapies. We have been encouraged by the preliminary evidence of anti-tumor activity against brain metastases observed in the Phase 1 study of GRN1005, and we hope to confirm these results in our Phase 2 trials.”

The purpose of GRABM-L Phase 2 study is to determine the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from Non-Small Cell Lung Cancer. The trial plans to enroll 50 patients, who will receive one intravenous dose of GRN1005 every three weeks (650 mg/m2). The primary efficacy endpoint for the trial is the response of the tumors to the drug during the course of treatment.

Patients with brain cancer, particularly secondary tumors that are the result of metastases, currently have few options. The reason for this treatment dead-end is the difficulty in getting antitumor drugs to effectively cross the blood-brain barrier and enter the tumor. Preclinical and Phase 1 data indicate that GRN1005 not only transports paclitaxel into tumors inside the brain through LRP1-mediated transport, but also has activity against tumors outside the brain.

Data on safety and tolerability, and preliminary evidence of anti-tumor activity of GRN1005 were documented in two separate Phase 1 multi-center, open-label, dose escalation clinical trials, conducted by Angiochem, Inc. In these trials, patients with heavily pre-treated progressing, advance-stage solid tumors and brain metastases (n=56; including NSCLC) and patients with recurrent or progressive malignant glioma (n=63) were treated with GRN1005. Final data were presented at the 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November. The data were encouraging. In patients with brain metastases from solid tumors, overall response rate was 20% (4/20) by one-dimensional assessment when treated with a dose of 650 mg/m2 of GRN1005 administered as single-agent therapy once every three weeks. Anti-tumor activity was observed against metastases inside the brain and in organs outside the brain, such as the liver, lung and lymph nodes.

Geron’s clinical development plan for GRN1005 includes two Phase 2 clinical trials in patients with brain metastases arising from either breast cancer (GRABM-B) or non-small cell lung cancer (GRABM-L). Top-line data from both studies are expected to be available by the end of the second quarter of 2013.

Combination Immunosuppressive Therapy Works Better for Stem Cell Treaments in Amyotrophic Sclerosis Patients

A research team from the University of California, San Diego has successfully grafted human spinal stems into the spinal cords of rats that have a rodent version of the neurodegenerative disease amyotrophic sclerosis (ALS). ALS is also known as Lou Gehrig’s Disease, which is progressive, degenerative, lethal, neuromuscular disease. In this study, the research group tested four different protocols that suppress the immune response to ensure that the transplanted cells were not attacked and rejected by the host animal’s immune system. The goal of this study was to determine which protocol improved the long-term therapeutic effects of the transplanted cells. This study demonstrated that a combined, systematically-delivered immunosuppression regimen of two drugs significantly improved the survival of the human spinal stem cells. Their results are published in the current issue of Cell Transplantation (20:8).

Michael P. Hefferan from the University of California, San Diego Neurodegeneration Laboratory and a corresponding author on the paper said, “There are no therapeutic strategies that successfully modify ALS progression or outcome. “Cell-based transplantation therapies have emerged as potential treatments for several neurological disorders, including ALS. However, cell graft survival seems to greatly depend on an accompanying immunosuppression regimen, yet there are differential responses to identical immunosuppressive therapies.”

The precise reason for this differential response is presently unclear, but the authors of this study suggested several mechanisms, including distinct types of acute and inflammatory responses, might be the primary reason for different efficacies of the same treatment. To address this possibility, the authors tried to optimize an immunosuppressive protocol for transplanting human spinal cord cells into rats that were genetically preprogrammed to develop ALS (ALS G93A rats). Two drugs, tacrolimus (FK506) and mycophenolate, were used to suppress the immune response against the transplanted spinal stem cells. These drugs were either used alone or in combination with each other.

Human spinal stem cells were transplanted before the ALS G93A rats started to show any ALS symptoms (presymptomatic). ALS G93A rats have a mutant superoxide dismutase gene. Superoxide dismutase is an enzyme found in every cell of our bodies and it detoxifies “superoxide radicals.” Superoxide radicals are oxygen molecules with an extra electron (O2-). Superoxide radicals form as a consequence of the chemical reactions cells use to make energy. Fortunately, our cells have enzymes, like superoxide dismutase, to convert superoxide radicals to hydrogen peroxide (H2O2). Hydrogen peroxide is degraded by the enzyme catalase to water and molecular oxygen. Without a functional superoxide dismutase enzyme, these rats sustain extensive cellular damage in their central nervous system, and, consequently, their motor neurons (those neurons responsible for voluntary movement) begin to die off.

Dr. Hefferan explained: “Although FK506 has been used successfully as monotherapy in our previous studies of spinal ischemia, it failed in the present study on ALS. In contrast to ALS, where spinal inflammation continues and likely worsens until endstage, the traumatically-injured spinal cord is typically characterized by an acute inflammatory phase followed by a progressive loss of most inflammatory markers.”

In this research project, those animals that received the combined immunosuppression of both FK506 and mycophenolate did better than those that received either drug alone and much better than those that received no immunosuppressive therapy. In all likelihood, the combination of the two drugs works better because of the longer drug half-life of mycophenolate rather than from its action. The addition of mycophenolate seems to supplement inhibition of T-cell formation, which leads to a robust survival of the grafted stem cells when analyzed three weeks after transplantation. This suggests that the extensive inflammation in the spinal cords of ALS patients requires extensive immunosuppressive therapies for transplanted stem cells to survive and provide regenerative effects.

HIV Drug Maraviroc Reduces Graft-Versus-Host Disease In Stem Cell Transplant Patients

A drug called maraviroc is normally used to treat Human Immunodeficiency Virus (HIV) infections, but work at the University of Pennsylvania suggests that maraviroc redirects the trafficking of immune cells. The significance of these results are profound for transplant patients, since a drug like maraviroc can potentially reduce the incidence of graft-versus-host disease in cancer patients who have received allogeneic (from someone else) stem cell transplantation (ASCT). This research, which was conducted at the Perelman School of Medicine at the University of Pennsylvania, was presented at the 53rd American Society of Hematology Annual Meeting.

Graft-versus-host disease or GvHD occurs as complication after a stem cell or bone marrow transplant. During GvHD, the newly transplanted cells recognize the recipient’s body as foreign and mount an attack against it. Acute cases of GvHD usually occur within the first 3 months after the transplant. Chronic GvHD usually starts more than 3 months after the transplant. GvHD rates vary from 30 – 40% among related bone marrow or stem cells donors and from 60 – 80% between unrelated donors and recipients. The greater the degree of immunological mismatches between the donor and the recipient, the greater the risk of GvHD. After a transplant, the recipient usually takes a battery of drugs that suppress the immune system. These drug treatments help reduce the chances or severity of GvHD.

Standard treatments for GvHD suppress the immune system. Commonly used medicines include methotrexate, cyclosporine, tacrolimus, sirolimus, ATG (Antithymocyte globulin), and alemtuzumab either alone or in combination. High-dose corticosteroids are the most effective treatment for acute GVHD. Antibodies to T cells and other medicines are given to patients who do not respond to steroids. Chronic GvHD treatments include prednisone, (a steroid) with or without cyclosporine. Other treatments include mycophenolate mofetil (CellCept), sirolimus (Rapamycin), and tacrolimus (Prograf). These treatments, if given during the course of the stem cell or bone marrow transplant, reduce but do not eliminate the risk of developing GvHD.

In the current trial, treatment with maraviroc dramatically reduced the incidence of GvHD in organs where it is most dangerous (liver, GI tract, lung, skin — without compromising the immune system and leaving patients more vulnerable to severe infections.

Assistant professor in the division of Hematology-Oncology and a member of the Hematologic Malignancies Research Program at Penn’s Abramson Cancer Center, Ran Reshef, commented: “There hasn’t been a change to the standard of care for GvHD since the late 1980s, so we’re very excited about these results, which exceeded our expectations. Until now, we thought that only extreme suppression of the immune system can get rid of GvHD, but in this approach we are not killing immune cells or suppressing their activity, we are just preventing them from moving into certain sensitive organs that they could harm.”

Reshef and colleagues presented results showing that maraviroc is safe and feasible in stem cell transplant patients who have received stem cells from a healthy donor. A brief course of the drug led to a 73% reduction in severe GvHD in the first six months after transplant, compared with a matched control group treated at Penn during the same time period (6% who received maraviroc developed severe GvHD vs. 22% of other patients receiving standard drug regimens).

Reshef explained, “Just like in real estate, immune responses are all about location, location, location. Cells of the immune system don’t move around the body in a random way. There is a very distinct and well-orchestrated process whereby cells express particular receptors on their surface that allows them to respond to small proteins called chemokines. The chemokines direct the immune cells to specific organs, where they are needed, or in the case of GvHD, to where they cause damage.”

Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma, myelofibrosis, and others, enrolled in the phase I/II trial. All patients received the standard GvHD prevention drugs tacrolimus and methotrexate, plus a 33-day course of maraviroc that began two days before transplant. In the first 100 days after transplant, none of the patients treated with maraviroc developed GvHD in the gut or liver. By contrast, 12.5% of patients in the control group developed GvHD in the gut and 8.3 percent developed it in the liver within 100 days of their transplant.

The differential impact of maraviroc on those organs indicates that the drug is working as expected, by limiting the movement of T lymphocytes to specific organs in the body. Maraviroc works by blocking the CCR5 receptor on the surfaces of lymphocytes. This prevents the lymphocytes from trafficking to certain organs. Maraviroc did not affect GvHD rates in the skin, which might mean that the CCR5 receptor is more important for sending lymphocytes into the liver and the gut than the skin.

After 180 days, the benefit of maraviroc appeared to be partially sustained in patients and the cumulative incidence of gut GvHD rose to 8.8% and the rates of liver GvHD rose only to 2.9%. The cumulative incidence of GvHD in the control group, however, remained higher, at 28.4% for gut and 14.8% for liver GvHD. Based on these data, the research team plans to try a longer treatment regimen with maraviroc to see if longer exposures to maraviroc can its protective effect.

Additionally, maraviroc treatment appeared to neither increase treatment-related toxicities nor alter the relapse rate of their underlying disease. Clearly this drug shows promise for limiting the devastating effects of GvHD in stem transplant patients.

Fate Therapeutics Clinical Trial with FT1050 Improves Stem Cell Engraftment In Umbilical Cord Blood Transplant Recipients

Patients who receive umbilical stem cell treatments after bone marrow-ablating cancer treatments usually have to wait for the cells the “engraft” or proliferate and fill the bone marrow. During this engraftment time, these patients are prone to life-threatening infections, since their immune systems are effectively wiped out. However, a natural compound called FT1050 (marketed as Prohema) might improve the ability of stem cells from umbilical cord blood to engraft in patients. A phase I clinical trial led by Dana-Farber Cancer Institute scientists provides genuine hope that this compound might decrease the engraftment time for umbilical cord stems cells.

FT-1050 (16,16-dimethyl Prostaglandin E2) is the first drug candidate from Fate Therapeutics’ platform of Stem Cell Modulators (SCMs). SCMs are small molecules that influence adult stem cells. By treating stem cell patients with SCMs, physicians hope to guide stem cells treatments toward desired outcomes, and these can include cell regeneration, healing or blocking cancer growth. In the case of blood cell-making stem cells (also known as “hematopoietic stem cells” or HSCs), FT1050 can mediate their ability to home to the bone marrow and eventually repopulate the patient’s blood and immune system. Because FT-1050 seems to affect fundamental pathways present in all blood cell-making stem cells, it could improve the efficiency and success of treatments with stem cells from any source, including from bone marrow, peripheral blood, and umbilical cord blood.

This clinical trial involved 12 patients who underwent reduced-intensity chemotherapy and then received a transplant of cord blood stem cells that had been treated with FT1050. FT1050-treated blood-forming stem cells might solve a long-standing problem with umbilical cord transplants – a relatively small number of stem cells are infused during such procedures, and therefore, they often take longer to engraft (or take root) in patients than do the more numerous stem cells involved in transplants from adult donors. These delays during engraftment can leave patients susceptible to dangerous infections and other complications.

Trial leader Corey Cutler, MD, MPH, of Dana-Farber and Brigham and Women’s Hospital put it this way: “There is a significant need to improve the speed and quality of engraftment of cord-derived stem cells. FT1050 has shown the ability in preclinical research to activate hematopoietic [blood-forming] stem cells so they engraft more quickly and with a higher degree of success.”

Umbilical cord stem cell transplants are an excellent option for patients who do not have a closely-matched adult donor. Since the current pool of potential donors is smaller for non-Caucasians than for Caucasians, members of ethnic minorities tend to receive transplants from cord blood at a higher rate than Caucasians.

The goal of this phase I trial was to assess the safety of FT1050-treated cord blood cells in adult patients who receive umbilical cord blood stem cell transplants. Additionally, this trial determined if the treated cells show accelerated engraftment. In the 12 patients who participated in the trial, engraftment occurred approximately three to four days faster than normal. Also the patient’s levels of particular types of white blood cells (neutrophils) returned to normal in the patients after a median of 17.5 days, which is similar to the rate in standard stem cell transplants. Side effects of the FT1050-treated cord blood cells were minimal, and in none of the study patients did the stem cells fail to engraft.

The phase I trial was sponsored by Fate Therapeutics, Inc., of San Diego, Calif., which is developing ProHema, a biologic product that consists of blood cell-making stem cells treated with FT1050 for patients who require a stem cell transplant. FT1050 was identified by Leonard Zon, MD, a hematologist and director of the Stem Cell Program at Children’s Hospital Boston, who used a chemical screens that was conducted in zebrafish. FT1050 is the first potential therapeutic derived from a zebrafish model to make it to clinical trials.

“We’re encouraged by the results of this study for patients receiving umbilical cord stem cell transplants after reduced-intensity chemotherapy treatment,” Cutler says. “Further studies are planned to test FT1050-treated hematopoietic stem cells in a larger group of these patients.”

StemCells, Inc. Announces Completion of Enrollment of Its First Cohort in Their Chronic Spinal Cord Injury Trial

StemCells, Inc. announced on December 15, 2001 that the first cohort of the Company’s Phase I/II clinical trial in chronic spinal cord injury have been successfully transplanted with the Company’s proprietary HuCNS-SC neural stem cells. This is a landmark clinical trial that has a unique design. What makes this clinical trial unique is the implantation of patients with progressively decreasing severity of spinal cord injury that are treated three sequential cohorts. The first cohort of patients all have spinal cord injury classified as AIS A, which is the most severe type of spinal cord injury as defined by the American Spinal Injury Association Impairment Scale or AIS.

Stephen Huhn MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells, Inc. made this statement: “We are extremely pleased with our progress in this innovative trial. Having completed dosing of the AIS A cohort, screening for AIS B patients, who have a less severe, incomplete type of spinal cord injury, can now begin. Of course, our first priority is to assess safety in each patient, but we will also be evaluating trial patients for changes in sensation, motor and bowel/bladder function.”

Martin McGlynn, President and CEO of StemCells Inc added, “I am also pleased to announce that, in consultation with the clinical team at Balgrist Hospital (University of Zurich), the Company has decided to open enrollment for the remainder of the trial to patients living in the United States and Canada. We have received a large number of inquiries from patients in both countries, and hopefully this decision will come as good news to the spinal cord injury community, who were greatly disappointed by Geron’s recent decision to discontinue its spinal cord injury trial. We remain optimistic about the prospect of being able to demonstrate safety and clinical utility of our cells in this devastating condition, and are committed to funding our spinal cord injury program until such time as we can come up with a definitive outcome.”

The Phase I/II clinical trial of StemCells, Inc.’s HuCNS-SC purified human adult neural stem cells is designed to assess both safety and preliminary efficacy of this cell line in the treatment of spinal cord injuries. Twelve patients with thoracic (chest-level) neurological injuries at the T2-T11 level are planned for enrollment. The first three patients all have injuries classified as AIS A, in which there is no apparent neurological function below the level of spinal cord injury. The planned second and third cohorts will consist of patients who have spinal cord injuries classified as AIS B and AIS C, which are less severe than AIS A spinal cord injuries and show at least some preservation of sensory or motor function. This trial will assess safety of the cell line and treatment efficacy based on specific criteria. These clinical criteria include changes in sensation, motor and bowel/bladder function. Prior to implanting the next cohort, data from previous cohorts will be reviewed by an independent Data Safety Monitoring Committee.

All patients will receive HuCNS-SC cells through direct transplantation into the spinal cord and will receive initial doses of medicines that suppress the immune system to ensure that the implanted cells do not elicit inflammation or are instantly rejected by the immune system. However, these drug treatments are temporary, since the central nervous system is surrounded by a blood-brain barrier than prevents the immune system from rejecting transplantations into the central nervous system. Temporary treatment with immunosuppressive drugs are necessary at the beginning of the procedure because the implantations breach the blood brain barrier and until this breach heals, the immune system has access to the implantation, but after the breach heals, immunosuppression is no longer necessary. Implanted patients will be evaluated regularly in the period after the transplant in order to monitor and assess the safety of the HuCNS-SC cells and the implantation procedure, and to determine if there are any neurological changes in the patients. The Company intends to follow the effects of this therapy long-term, and a separate four-year observational study will be initiated at the conclusion of this trial.

The trial is being conducted at Balgrist University Hospital, University of Zurich, a world leading medical center for spinal cord injury and rehabilitation. This institution has a global reputation for providing some of the highest quality examinations, treatments and rehabilitation opportunities to patients with serious musculoskeletal conditions. The clinic owes its leading international reputation to its unique combination of specialized medical services. The hospital’s carefully balanced, interdisciplinary network brings together under one roof medical specialties including orthopedics, paraplegiology, radiology, anesthesiology, rheumatology, and physical medicine.

Induced Pluripotent Stem Cells Produce Pigs That are Superior Model Systems for Medical Research

Rodents are the standard laboratory model system for testing the safety of treatments, chemicals and other medically important protocols and devices. Rodents share an immune system that is very similar to the primate immune system, and also share many other biological features with primates. However, all the drugs we ingest usually make a stop at the liver where they are chemically modified, and this modification step differs from rodents to humans. Some drugs are processed in very similar manners in rats, mice and humans, but many other drugs are processed quite differently. In such cases, rodents make poor model systems for how those drugs might affect human patients.

Another case where rodent models are less than exemplary is cancer studies. Experiments on rodents and rodent-derived cell lines have provided vital insights into the genetics, cell biology and molecular biology of cancer, carcinogens, or compounds that cause cancer in living organisms, have very different effects in rodents and humans. For example, some components in coffee appear to be carcinogenic in rodents, but in humans moderate coffee consumption may reduce the risk of cancer.

Another field of research trends to show very different results in humans and rodents and that field is stem cell research. Induced pluripotent stem cells (iPSCs), which are embryonic-like stem cells made from adult cells though genetic engineering techniques, very effectively cause tumors in rodents. However, in 2010, University of Georgia scientists Steve Stice and Franklin West introduced 13 pigs that might show the way toward new regenerative therapies. These pigs have been the subjects of some experiments with iPSCs and the astounding result is that adult-cell-sourced stem cells (iPSCs) don’t form tumors in these pigs.

West, an animal science researcher and assistant professor in the UGA College of Agricultural and Environmental Sciences said: “Pluripotent stem cells have significant potential for stem cell therapies . . . However, tests in mice often resulted in tumor formation that frequently led to death.” Such robust tumor formation raised concerns about the safety of iPSCs and any cells derived from iPSCs. However, to date, the vast majority of these safety tests have been done in rodent models. Given the rodents can show different results in carcinogenesis tests (a test that determines the tendency of a chemical to cause cancer) relative to humans, West and Stice wondered if these differences as translated into tumor tests with iPSCs.

To address this concern, West and Stice, and their research colleagues examined tumor formation in pigs that were actually made from iPSCs. The results were striking. According to West, “Brain, skin, liver, pancreas, stomach, intestine, lung, heart, kidney, muscle, spleen and gonad tissues from all 11 pigs tested showed no evidence of tumors.” The absence of tumor formation in these pigs suggests that iPSCs can safely incorporate into tissues without causing the formation of tumor.

The potential of such animals as model systems for medical purposes is not lost on these scientists. Steve Stice, a Georgia Research Alliance Eminent Scholar in the College of Agricultural and Environmental Sciences, said: “Being able to safely use iPSCs without the potential of causing tumors is essential for this promising stem cell therapy to become a viable treatment option . . . We now have graduate students working on making neural cells from the human and pig stem cells to help further the studies. The human stem cells were effective in a rodent model for stroke, but rodent studies are not rigorous enough to start human clinical trials.”

There are over 700 drug treatments that have gone to human clinical trials for stroke alone based on safety tests that were done on rodents. However once these drugs were brought to clinical trials, they failed all safety tests. These pigs, however, are much more similar to humans when it comes to drug processing and tolerance. Such animals are much better model systems to study strokes than rodents.

West is leading a cooperative project between the UGA Regenerative Bioscience Center and stroke researchers at Georgia Health Sciences University. “This project will improve the speed and efficiency of treatment development for stroke and many other conditions and potentially reduce the number of nonhuman primates used in research,” he said. In addition to this collaboration, Stice and West have now bred the pigs produced from iPSCs and have demonstrated that the stem cells did form germ cells (eggs and sperm), and their genes were passed to their offspring. These data opens the door for better animal-sourced tissue for human regenerative medicine such as islet cells that produce insulin for diabetic patients.

Using iPSC technology, the UGA Regenerative Bioscience Center is working with researchers at Emory University to make pigs whose cells from the pancreas demonstrate decreased rejection in human treatments. Stice noted, “The next step would be to put these pig insulin-producing cells into other animals, potentially dogs or cats suffering from diabetes—to see if it will produce insulin for them without being rejected . . . So, it’s moving forward. Never as fast as we like, but it’s moving.”

Determining the Origins of Blood cell-Making Stem Cells

Nancy Speck, professor of Cell and Developmental Biology at the Perelman School of Medicine at the University of Pennsylvania, and her team have discovered a molecular marker for the immediate precursors of blood-making stem cells in the developing embryo. This discovery provides insights that may eventually help biotechnology companies make blood-making stem cells by means of tissue engineering.

Blood making stem cells are found in the bone marrow of adults, and these stem cells produce all the blood cells found in blood. A deeper understanding of these cells may allow scientists to someday manipulate or even make blood-making stem cells for therapy. Speck and her colleagues stated: “The ultimate goal for stem-cell therapies is to take precursor stem cells and push them down a particular lineage to replace diseased or dead cells in human adults or children . . . You have to understand how this happens in the embryo.”

Previous studies strongly suggested that blood-making stem cells originated from a small population of cells that line blood vessels (endothelial cells). However, it is unclear precisely which endothelial cells transition to blood stem cells during early development. During embryonic development, multiple waves of blood-cell development occur. The first wave gives the embryo a quick source of oxygen, and the final wave sets up the development of blood-making stem cells that ultimately reside in adult bone marrow. Laboratory techniques can produce the first wave of blood cell progenitors from embryonic or induced pluripotent stem cells. However, efforts to produce blood-making stem cells have failed. By understanding the developmental origins of blood-cell forming stem cells, scientists can potentially produce them in the lab from embryonic or induced pluripotent stem cells.

How much closer does this study bring hematologists and other scientists to making blood cell-making stem cell stem cells in the laboratory? Presently, scientists can make blood cells from endothelial cells, and they can monitor such cells in the embryo. Not all endothelial cells can produce blood-cell forming stem cells. To find those cells that can form blood-cell forming stem cells, Speck’s team used a special marker to follow their development. Progenitor cells in the first wave of embryo blood-cell development and the blood-cell forming stem cells of later waves of development are differentiated from distinct populations of blood-producing endothelial cells by the expression of a marker called “Lya6a.” This marker is expressed in those endothelial cells that eventually form blood-cell forming stem cells and is not expressed in those endothelial cells that make the first wave of blood cells.

Knowing more about the development of blood cell-making stem cells and its distinct markers can help tissue engineers make blood cell-making stem cells in the lab for stem-cell therapies. Some leukemia patients cannot find suitable donors bone marrow donors, and these studies might help clinicians potentially patient’s own cells to make blood-cell forming stem cells to replace their diseased stem cells. Eventually, such techniques can even be used to make blood cells depleted by chemotherapy or blood cancers. Such technologies might be applicable to other treatments as well.

The Protein Ephrin Herds Muscle Stem Cells to Form Adult Muscle

Satellite cells are dormant stem cells in skeletal muscles that come alive when the muscle is damaged. Do satellite cells from distant sites converge upon damaged muscle sites, or does muscle repair depend on locally available satellite cells? Also, if muscle is repaired by local and more far-flung satellite cell populations, what is the signal that wakes satellite cells from their slumbers and brings to them to damaged area? Furthermore, can we manipulate these signals to bring satellite cells to muscles that need healing but are not damaged in a manner that satellite cells can effectively detect? Knowing the answers to questions like these could potentially allow researchers to treat muscle disorders such as muscular dystrophy, in which the muscle is easily damaged and the patient’s satellite cells have lost the ability to repair.

Researchers from the Cornelison lab at the University of Missouri, Columbia have used time-lapse microscopy to follow precisely the movement of the satellite cells over various substrates that were painted onto glass slides. By watching satellite cells move over the stripes of substrates, Cornelison and her colleagues discovered that a protein called “ephrin” is a repulsive signal for satellite cells. When satellite cells that were placed on glass slides encountered striped of ephrin protein, those cells would touch the ephrin stripes and immediately turn around and travel in a new direction.

The significance of this finding is not lost on Cornelison, who commented: “There is currently no effective satellite cell-based therapy for muscular dystrophy in humans. One problem with current treatments is that it requires 100 stem cell injections per square centimeter, and up to 4,000 injections in a single muscle for the patient, because the stem cells don’t seem to be able to spread out very far. If we can learn how normal, healthy satellite cells are able to travel around in the muscles, clinical researchers might use that information to change how injected cells act and improve the efficiency of the treatment.”

How is ephrin directing satellite cell migration? Cornelison hypothesize: “Because the long, parallel muscle fibers carry these ephrin proteins on their surface, ephrin might be helping satellite cells move in a straighter line towards a distant ‘mayday’ signal.”

Further work on satellite muscle cells by Cornelison’s lab showed that when they gave cultured satellite cells signals to differentiate and fuse to form muscle fibers in culture, they could simultaneously use painted striped of ephrin proteins to herd the cells into parallel arrays. This is a striking find because muscle fibers always form parallel arrays in living organisms, but no one has been able to persuade muscle fibers to do this very thing in culture. Thus, it is entirely possible that ephrins are one of the major molecules that regulate several of the different steps required to move a population of stem cells that are spread out all over the muscle, to an organized, properly patterned new muscle fiber.

“We are really excited about the potential of these findings to explain a lot of things that were puzzling about the way satellite cells behave in healthy muscle, compared to a muscular dystrophy patient’s own cells, or cells that have been injected therapeutically,” Cornelison said. “If we’re really lucky, we could find something that could make a difference in these kids’ lives, and that’s what we want the most.”

The Source of Your Mesenchymal Stem Cells Matters

Mesenchymal stem cells (MSCs) are found throughout the body. The most well-known source of MSCs is the bone marrow, and bone marrow MSCs are sometimes called “stromal cells,” because they compose a major part of the bone marrow stroma. In bone marrow, the stroma does not directly participate in making blood cells, but it greatly influences blood cell making by providing the proper microenvironment for blood cell making. Bone marrow MSCs produce a host of molecules called “cytokines” that have a significant effect on blood cell production.

However, bone marrow is not the only source of MSCs. MSCs are also found in fat tissue, liver and connective tissue, blood vessels, and umbilical cord. Are all these MSCs the same? This is not a trivial question because regenerative medicine often requires cells with various capacities. Bone treatments require cells that are the best at making bone tissue, heart treatments require cells that are the best at making heart muscle, and vascular disorders require cells that are the best at making blood vessels. Physicians must know the precise abilities of the cells available to them so that they can select the most effective treatment. Therefore, it is incumbent on scientists to properly characterize MSCs from different sources in order to determine what they can and cannot do. It is also important to establish it MSCs from multiple sources are all the same or have genuinely distinct properties.

A paper in the journal Stem Cells and Development examines MSCs from bone marrow and umbilical cord connective tissue (known as Warton’s Jelly) and extensively characterizes them (Hsieh, et al., Stem Cells and Development 2010, 19(12): 1895-910). The differences between these two cell populations are somewhat surprising.

Jui-Yu Hsieh,and his colleagues at National Yang-Ming University, Taipei, Taiwan subjected MSCs from bone marrow and umbilical cord to differentiation tests and examined the gene expression profile from both cell populations. They discovered that both bone marrow MSCs and umbilical cord MSCs had the same cell surface proteins.  However, the similarities ended there.  Bone marrow MSCs were superior to umbilical cord MSCs when it came to forming fat cells. The bone marrow MSCs showed a higher proportion of the cells forming functional fat cells and bone marrow MSCs also expressed fat cell-specific genes much more robustly than umbilical cord MSCs.

Next, this research group dissected the genes made by both cell populations. In this case, the results showed marked differences between the two cell types. Umbilical cord MSCs expressed more neural genes than their bone marrow counterparts, and also expressed several genes involved in making blood vessels. Umbilical cord MSCs also made more of the genes typically expressed in embryonic stem cells. This suggests that umbilical cord MSCs should grow better in culture than bone marrow MSCs, and in growth comparisons in culture, umbilical cord MSCs substantially outgrew bone marrow MSCs. Bone marrow MSCs, on the other hand, made lots of genes involved with making bone tissue, and also expressed genes involved in the immune system.

In order to determine if the gene expression differences between these MSCs translated into behavioral differences in culture, the two populations of MSCs were grown in culture and subjected to protocols to differentiate them into bone. As expected, the bone marrow MSCs greatly outperformed the umbilical cord MSCs when it came to bone differentiation. Likewise, when the two different cell populations were tested for activating the immune system of a host animal, the bone marrow MSCs were much more easily recognized by the immune system of the host animal than their umbilical cord counterparts.

There are several controversies that have emerged with the publication of this paper.  First of all, an earlier paper (Clavarella, et al., Stem Cells and Development 2009, 18: 1211-20) showed that umbilical cord MSCs formed bone as well as bone marrow MSCs.  However, in this paper, a side-by-side comparison was not done, which suggests that the results reported in this earlier paper are not as trustworthy as in this later work.  Secondly, the cell culture results in the later paper exactly parallel the gene expression data.  Also, another publication (Ishige, et al., International Journal of Hematology 2009, 90: 261-9) showed that umbilical cord stem cells taken from Warton’s Jelly possess the lowest capacity to form bone tissue in comparison to MSCs taken from umbilical veins or arteries.  This further corroborates the data in this later paper.

These data from this paper confirms something that clinicians have observed time and time again; namely that bone marrow MSCs are the best material for repairing joints and other musculoskeletal conditions. Also, this paper definitively demonstrates the vast gene expression differences between these two populations of MSCs. While several papers have shown distinct differentiation differences between various populations of MSCs from different sources, this paper shows that the profound differences in gene expression underlay these biological differences.  Furthermore, this work establishes that where you get your MSCs matters when it comes to using them for regenerative medicine.

Repairing Spinal Cord Injury With Dental Pulp Stem Cells

In a recent study, Akihito Yamamoto and colleagues, at Nagoya University Graduate School of Medicine, Japan used human dental pulp stem cells to treat rats with severe spinal cord injury. When these spinal cord-injured rats were transplanted with human dental pulp stem cells, they showed marked recovery of hind limb function. Detailed analysis of the implanted tissue revealed that the human dental pulp stem cells mediated their restorative effects in three ways: they inhibited the death of nerve cells and their support cells; they promoted the regeneration of severed nerves; and they replaced lost support cells by generating new ones. Yamamoto and colleagues therefore hope that this approach can be translated into an effective treatment for severe spinal cord injury

One of the most common causes of disability in young adults is spinal cord injury. Currently, there is no proven reparative treatment.  These experiments by Yamamoto and his colleagues potentially give some hope to spinal cord injury patients that a stem cell population, specifically dental pulp stem cells, might be of benefit them someday.

Scalable Amounts Of Liver And Pancreas Precursor Cells Created Using New Stem Cell Production Method

Canadian scientists have managed to overcome a key research obstacle to developing regenerative treatments for diabetes and liver disease. This breakthrough utilizes a technique to produce medically useful amounts of endodermal cells from human pluripotent stem cells. This research, which was published in Biotechnology and Bioengineering, is transferable to other areas of stem cell research, and might help scientists find a way to move stem cell treatments from the bench to the clinic.

Dr Mark Ungrin from the University of Toronto said: “One million people suffer from type 1 diabetes in the United States, while liver disease accounts for 45,000 deaths a year. This makes stem cells, and the potential for regenerative treatments, hugely interesting to scientists. Laboratory techniques can produce thousands, or even millions, of these cells, but generating them in the numbers and quality needed for medicine has long been a challenge.”

This work examined using pluripotent stem cells (PSC) to generate endoderm cells. During early embryonic development, the embryo undergoes a remarkable rearrangement process called “gastrulation. Prior to gastrulation, the embryo is one cell layer thick. After gastrulation, the embryo is three cell layers thick. The outer cell layer is called “ectoderm,” and it forms the skin, and the nervous system. The cell layer underneath the ectoderm is the mesoderm, which forms most of the internal organs like bones, muscles, glands, kidneys, reproductive organs, and connective tissue. The lowest layer of cells is the endoderm, which forms the gastrointestinal tract and its associated organs, and the lungs. These three cell layers – ectoderm, mesoderm, and endoderm – are called the “three primary germ layers,” and they form all the internal organs of the body. The ability to differentiate, or transform, PSCs into endoderm cells is a vital step to developing regenerative treatments for these organs.

Ungrin noted: “In order to produce the amount of endoderm cells needed for treatments it is important to understand how cells behave in larger numbers, for example how many are lost during the differentiation process and if all the cells will differentiate into the desired types.”

The technique used by this research team stained cells with vital dyes that allowed them to determine the efficiency of endodermal differentiation. This technique allowed the team to detect cell inefficiencies and develop a new understanding of the underlying cell biology during the differentiation of PSCs into endodermal precursors. This allowed the team to increase effective cell production 35-fold. These results showed significant increases in the quantity of endodermal cells. It also allows workers to scale up the production of useful cells, and ensures PSC survival and effective differentiation. Since creating sufficient quantities of endodermal precursors is one of the bottlenecks of this research, overcoming this bottleneck can potentially help future stem cell researchers navigate the often long and challenging route from laboratory testing to clinical use. It could also accelerate the time from biomedical advance to beneficial therapy, often referred to as the bench-to-bedside process.

Ungrin opined: “Most research in this field focuses on the purity of generated cell populations; the efficiency of differentiation goes unreported. However our research provides an important template for future studies of pluripotent stem cells, particularly where cells will need to be produced in quantity for medical or industrial uses.”

Newly Discovered Heart Stem Cells Make Muscle And Bone

The research group of Richard Harvey of the Victor Chang Cardiac Research Institute in Australia has identified a new and relatively abundant pool of stem cells in the heart. This discovery was published in the December issue of Cell Stem Cell and shows that this pool of adult stem cells in the heart have the capacity to grow in culture outside the body and possess the ability to form many different cell types, including muscle, bone, neural and heart cells.

This discovery could lay the foundations for regenerative therapies that enhance tissue repair in the heart. Damaged heart muscle does no usually repair itself, and the incredibly hostile environment within the heart after a heart attack contributes to the wide-scale loss of cells, including stem cells, after a heart attack. According the Richard Harvey, “In the end, we want to know how to preserve the stem cells that are there and to circumvent their loss.”

These newly described cardiac stem cells are found in both developing and adult hearts, and, as in bone marrow and other organs, they are predominantly found in the vicinity of blood vessels. Harvey says despite the ability of these cells to form other cell types (a characteristic known as multipotency), these cells might have a bias toward producing heart-specific tissues. Their flexibility could be a byproduct of the need to remain responsive to the environment and to many types of injury. Harvey’s discovery comes at a time when stem cells harvested from human hearts during surgery are just beginning to show promise for reversing heart attack damage,

While cell-based therapies do have potential for repairing damaged heart tissue, Harvey ultimately favors the notion of regenerative therapies designed to tap into the natural ability of the heart and other organs to repair themselves. There is more work to do to understand exactly what role these stem cells play in that repair process. Harvey’s research team is now exploring some of the factors that bring those cardiac stem cells out of their dormant state in response to injury and protect their stem cell status.

LateTIME Trial Gives More Reason for Optimism Than Originally Thought

A recently completed clinical trial called the “LateTIME” trial examined the ability of bone marrow stem cell transplants into the heart after a heart attack to help heal the heart. While the study showed that such transplants were safe, they failed to show efficacy for this procedure. Nevertheless, the scientists who performed this study have re-examined their data and see reasons for optimism in this procedure.

The results from the LateTIME trial were reported at the 2011 American Heart Association (AHA) Scientific Sessions conference, and were also later published in the Journal of the American Medical Association (JAMA). While patients who received the treatments showed no more improvement than the group that was not injected with their own bone marrow stem cells, JAMA editors believe that these data give some reason for optimism.

First of all, some of the patients in the LateTIME trial showed effective recovery following bone marrow implantations. Furthermore, these patients who showed improvements tended to group with those patients who received their bone marrow treatments earlier rather than later. Therefore, it is possible that bone marrow implantations into the heart are potentially effective if they are given relatively soon after the heart attack.

Already the co-investigators who directed the LateTIME trial (Dan Simon and Marco Costa of UH Case Medical Center), are currently conducting in a similar trial called the “TIME” trial that already has reduced the time between attack and stem cell injection. The research team is optimistic that the time variable adjustment in the new trial will generate favorable outcomes. Dan Simon commented: “We have reason to believe, as supported by data, that an adjusted injection timeframe could yield stronger results and support for stem cell injections rebuilding damaged heart muscle and function.” Dr. Simon is the chief of Cardiovascular Medicine at UH Case Medical Center and the Herman K. Hellerstein Professor of Cardiovascular Research at Case Western Reserve University School of Medicine. Marco Costa sounded an additional optimistic note: “The results were not positive, but if you put it into perspective, the foundation or blueprint for success was discovered and that could certainly lead to advanced treatment options for these patients. Dr. Costa is the Director of the Interventional Cardiovascular Center and Research & Innovation Center at UH Case Medical Center, and also serves as Professor of Medicine at Case Western Reserve University School of Medicine.

Both clinical trials share a theory of heart repair. Namely that specialized stem cells in the bone marrow have the ability to promote blood vessel growth, prevent cell death and transform themselves into a number of tissues, including heart muscle. After an acute heart attack, a remodeling process is initiated in the heart in an attempt to compensate for the damaged areas. It is highly probable that the condition of the heart muscle several weeks after a heart attack differ considerably from the heart muscle in the acute stage setting. In fact, for some patients delaying the delivery of stem cells by two to three weeks may have been better than initiating the treatment during the acute phase.

All patients who participated in the LateTIME study underwent baseline assessments that included medical history, physical exam, electrocardiogram, blood draws, and MRI tests. Participants were then assigned randomly to receive the stem cells or placebo within the previously mentioned two – three-week timeline. The morning of stem cell or placebo infusion, a blood draw and bone marrow aspiration procedure of the hip bone are conducted to collect the stem cells. Later the same day, either stem cells or placebo are then infused through a catheter and directly into the damaged area of the heart. Following the first 24 hours of the infusion, participants wear a small ECG machine, or Holter monitor. Additionally, patients record their body temperature twice a day for 30 days post infusion. Follow up visits at one month, three, six, and twelve and twenty-four months after the procedure, during which baseline assessment tests are conducted. The TIME trial adjusts that variable and results of this trial will be published in two years.

Delayed Bone Marrow Transplantations Following Heart Attacks Is Safe But Not Effective

The LateTIME study (Transplantation In Myocardial Infarction Evaluation) rigorously examined the safety and effectiveness of whole bone marrow cell transplantations into the heart after a heart attack. This study definitively established the safety of this procedure, but it was not able to demonstrate the effectiveness of it.

LateTIME study participants received bone marrow transplants two-three weeks after suffering from a heart attack. Between July 2008 and February 2011, 87 people who had suffered heart attacks were enrolled in the LateTIME study. All patients had undergone cardiac procedures to open blocked arteries, and had moderate to severe impairment in their left ventricles, the heart chamber that pumps oxygen-rich blood from the heart to the systemic circulation where the blood flows through the body. All participants had stem cells taken from bone marrow in their hip for processing. LateTIME researchers developed a standardized method of processing and purifying bone marrow stem cells, and this was the first BMC trial to provide a uniform dose of BMCs to each participant. The study also randomly assigned the participants to receive either their purified BMCs or inactive (placebo) cells.

Several previous studies have suggested that injecting BMCs into the heart can improve cardiac function following a heart attack and perhaps reduce the need for future hospitalizations and heart surgeries. In contrast to LateTIME, earlier studies delivered BMCs within a few days of the heart attack. In many cases, a patient will not be able to get such immediate treatment, due to poor health following a heart attack or because the hospital providing care doesn’t have a stem cell therapy program.

“Although treatment and survival following a heart attack have improved over the years, the risk of heart failure following a heart attack has not decreased,” said Susan B. Shurin, M.D., acting director of the NHLBI. “Stem cell therapy is a promising direction for repairing the damage done by a heart attack. We do not fully understand the optimal use of these cells; studies like LateTIME will help us understand how to perform and monitor these procedures.”

After six months, improvement of heart function was assessed by measuring the percentage of blood that gets pumped out of the left ventricle during each contraction (left-ventricular ejection fraction, or LVEF) by cardiac MRI. There were no significant differences between the change in LVEF readings between baseline and six months in the BMC (from 48.7 percent to 49.2 percent) or placebo (from 45.3 percent to 48.8 percent) groups.

“This does not mean that stem cell therapy will only work if done immediately following a heart attack or that later beneficial effects on clinical outcomes won’t emerge,” noted Lemuel A. Moyé , M.D., Ph.D., professor of biostatistics at the University of Texas School of Public Health, Houston, and a LateTIME researcher. “Many factors influence how the heart responds to stem cells, which highlights the critical need to continue rigorous tracking studies in this area.” Moyé also added that the health of the study participants will continue to be evaluated for two years, so the BMC therapy may yet demonstrate health benefits such as a lower risk of subsequent heart attacks or heart failure, in which the heart cannot pump enough blood to meet the body’s needs.

LateTIME is one of three heart stem cell trials being undertaken by the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network. The other trials under way by this multicenter consortium are TIME, which compares the effectiveness of stem cell therapy delivered at three days versus seven days following a heart attack, and FOCUS, which examines stem cell therapy in people with chronic heart failure.

This study and several others seem to establish that whole bone marrow is simply not as effective for treating heart attack patients as specific stem cell populations. Bone marrow stem cells are a very heterogeneous population, and specific populations of bone marrow stem cells must be isolated, expanded, and conditioned for heart muscle/blood vessel differentiation before they can be used. These specific stem cell populations are almost certainly much more effective than whole bone marrow, which contains a variety of cells that almost certainly cannot survive in the oxygen-poor environment of the heart after a heart attack.

Centeno Stem Cell Treatment Featured in ESPN Magazine

Christopher Centeno runs a stem-cell based orthopedic clinic in Broomfield, Colorado.  In 2010, NFL defensive end Jarvis Green visited Centeno after Green had experienced two failed knee surgeries. Green faced the end of his eight-year career with the New England Patriots.  Then Centeno performed his Regenexx-C procedure on Green, and he is a new man.

Shortly after receiving his stem cell treatment, Green was back in the NFL. “Before, I couldn’t walk up the stairs,” Green told The Mag. “Three weeks later, I went to an NFL training camp and didn’t miss a day.” Green’s procedure has been featured on and in the ESPN Magazine.  Green’s football career has been saved and he is sold on stem cell treatments.

Unfortunately, not everyone is happy about Green’s successful recovery and not everyone is applauding Centeno’s procedure.  The first unhappy onlooker is the United States Food and Drug Administration (FDA).  In August 2010, the FDA filed a federal injunction to prevent Centeno from culturing stem cells from patients.  The FDA claims that Centeno was “adulterating” blood in a way that turned it into an unapproved new drug.  Centeno, who still provides same-day stem cell procedures, has spent $500,000 fighting the agency’s controversial opinion and even more money moving his culturing operation to a new clinic offshore in the Cayman Islands where the FDA cannot hassle him.  Centeno told the ESPN Magazine, “The FDA has pushed this therapy out of the U.S.”

First of all, the FDA’s claim is bogus, bordering on stupid.  Regenexx takes the bone marrow stem cells (mesenchymal stem cells) and cultures them for about 6 weeks.  This is part of what Regenexx calls the “Regenexx-C” procedure.  These cultured and expanded mesenchymal stem cells are precisely applied to the joint, tendon or cartilage surface that requires repair.  Then the stem cells are allowed to work their healing ways. Somehow, the FDA thinks that culturing mesenchymal stem cells and expanding them in culture sufficiently changes them so that they now constitute a drug, and therefore the FDA gets to regulate it.  Excuse me FDA, BUT IT’S THE PATIENT’S CELLS.  BUTT OUT!!!!  Seriously folks, this is just one of umpteen hundred some-odd stories of the FDA’s stupidity, and overstepping their bounds.  Our FDA needs serious reformation and they need to set discrete limits on what they can and can’t regulate.  How can these naturopathic quacks give all manner of herbal concoctions to their patients without the FDA making a sound while Centeno gives people their own cells and the FDA says that they are getting an unapproved drug?  Clearly this is bureaucratic nonsense.

The secondly unhappy camper is Theodore Friedmann, a geneticist at the University of California, San Diego who heads the World Anti-Doping Agency’s (WADA) gene doping panel and has been given the job of advising WADA on stem cell policy.  Friedmann wrote, “There’s very little evidence that bone marrow stem cells taken from one site and injected into another will do anything. . . The most likely outcome is that if you put stem cells in places that are unfamiliar to them, like a knee or shoulder, most of them will just die.”  Both of these statements drip with ignorance.  In the case of orthopedic usages of mesenchymal stem cells, there is a copious literature of experiments on laboratory animals that shows that extracted mesenchymal stem cells from bone marrow can help heal joint abnormalities (CJ Centeno & SJ Faulkner, “Regenerative Orthopedics” in Advances in Regenerative Medicine, edited by Sabine Wislet-Grendebien,  InTech, 2011, 349-362).  Secondly, there is a gradually accumulating corpus of literature that shows that the use of expanded mesenchymal stem cells from bone marrow reduces symptoms in patients with hip or knee problems (Centeno et al., Pain Physician 9(3): 253-6; Centeno et al., Pain Physician 11(3): 343-53; Centeno et al., Medical Hypotheses 71(6): 900-8), and causes few side effects (Centeno et al., Current Stem Cell Research Therapy 5(1): 81-93).  Centeno and his group have tracked over 339 patients who have received his procedure for up to three years and none of them have shown any tumors or ectopic tissue growth.  Likewise and 11-year study of 45 different knees in 41 different patients that were treated with their own bone marrow mesenchymal stem cells showed effective treatment of knee injuries and a lack of side effects (Wakitani, et al., Journal of Tissue Engineering and Regenerative Medicine 5(2): 146-150).  Another study examined cultured bone marrow mesenchymal stem cells that were reimplanted into the knees of patients with articular cartilage defects in platelet-rich fibrin.  The results showed evidence of healed cartilage in most of the patients 12 months after the procedure (Haleem, et al., Cartilage 1(4): 253-261).  So much for “there’s very little evidence that bone marrow stem cells taken from one site and injected into another will do anything.”

Friedmann’s second statement, “The most likely outcome is that if you put stem cells in places that are unfamiliar to them, like a knee or shoulder, most of them will just die,” shows that he clearly does not understand the procedure used by Centeno and others.  Regenexx uses MRI-guided injection systems to precisely implant stem cells at the location where they are needed.  Centeno himself has blasted the use of blind stem cell injections into the knee.  Because the stem cells are delivered to precisely the point of need, they do not move far from the point of injection, and they do what they need to do at the point of injury.  This is a significant part of the success of the Regenexx method, as is the conditioning of the stem cells with platelet-enriched plasma that the FDA erroneously thinks is a drug.  This is not scatter-shot introduction of stem cells into a joint, but it is a genuine point-of-defect delivery of healing stem cells.

All in all, the Regenexx procedure has helped some serious athletes recover the use of their joints and earn their living.  These procedures have been shown to be safe and effective, at least in some patients.  The United States should allow these clinics to run their procedures in the country.  It would provide a significant source of revenue when our economy seriously needs it and to disallow it because of some cock-and-bull-fairytale about cultured mesenchymal stem cells being a drug is a perfect example of the kind of over-regulation that is killing innovation in our country and stripping our economy of the things that can make it great again.  In November we need to go to the pools and throw this present government out on their ears.