Medistem Inc issued a press release describing a collaborative publication between the University of California San Diego, Indiana University, University of Utah, the Dove Clinic for Integrative Medicine, Biotheryx, NovoMedix, The Bio-Communications Research Institute, The Center for Improvement of Human Functioning International and Aidan Products, discussing the contribution of circulating endothelial cells to prevention of aging. The publication also provided data showing that healthy volunteers who have been administered the food supplement Stem-Kine had a doubling of circulating endothelial progenitor cells.

The paper "Circulating endothelial progenitor cells: a new approach to anti-aging medicine?" is freely accessible. "Numerous experiments and clinical trials have been published describing the importance of these repair cells that the body possesses to heal internal organs," stated Dr. Doru Alexandrescu from Georgetown Dermatology, a co-author of the publication. "However, to our knowledge, this is the first comprehensive blueprint in the peer-reviewed literature of how this knowledge may be applied to the question of aging."

The paper summarizes publications describing correlations between decline of circulating endothelial cells and aging/deterioration of several organ systems. The main hypothesis of the publication is that the bone marrow generates a basal number of circulating endothelial cells that serve to continually regenerate the cells that line the blood vessels. Many diseases that are prevalent in aging such as Alzheimer’s are associated with dysfunction of the blood vessel’s ability to respond to various stimuli. This dysfunction is believed to be caused by diminished numbers of circulating endothelial progenitor cells.

Other conditions such as peripheral artery disease are also associated with reduction in this stem cell population, however, when agents are given that increase the numbers of these cells, the degree of atherosclerosis-mediated pathology is decreased. This was demonstrated in a study that administered the drug GM-CSF, which causes an increase in circulating endothelial progenitor cells in a manner similar to Stem-Kine. Unfortunately, drugs currently on the market that have this ability are very expensive and possess the possibility of numerous side effects. The Stem-Kine food supplement is sold as a neutraceutical and is made of natural ingredients that have already been in the food supply.

Another interesting point made by the paper was that the body modulates the number of circulating endothelial progenitor cells based on need. In stroke, the number of circulating endothelial progenitor cells markedly increases in response to the brain damage. Patients in which a higher increase is observed are noted to have a higher chance of recovery. Therapeutic interventions that contain endothelial progenitor cells such as administration of bone marrow cells after a heart attack, are believed to work, at least in part, through providing a cellular basis for creation of new blood vessels, a process called angiogenesis.

Patients with inflammatory conditions ranging from chronic heart failure, to type 2 diabetes, to Crohn’s disease are noted to have a reduction in these cells. The reduction seems to be mediated by the inflammatory signal TNF-alpha. Studies reviewed in the paper describe how administration of antibodies to TNF-alpha in patients with inflammatory conditions results in a restoration of circulating endothelial progenitor cells.

In addition to the possible use of Stem-Kine for restoration/maintenance of circulating endothelial progenitor cells, the publication discusses the possibility of using such cells from sources outside of the body, for example cord blood. Although it was previously thought that cord blood can be used only after strict HLA matching, recent work supports the idea that for regenerative medicine uses, in which prior destruction of the recipient immune system is not required, cord blood may be used without immune suppression or strict tissue matching. This is discussed in the following paper: Cord blood in regenerative medicine: do we need immune
suppression?.

Bone marrow cells contain several populations that are useful for regenerating injured/aged tissue. These cells include hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, and some argue, progenitor cells left over from embryonic periods that are still capable of differentiating into numerous injured tissue. It has been known for some time that bone marrow cells are capable of treating liver failure both in vitro and in early clinical trials, as can be seen on this video: Stem Cell Therapy for Liver Failure. Other types of stem cells useful for treatment of liver failure, such as cord blood stem cells, may be seen on this video: Cord Blood and Bone Marrow Stem Cells for Liver Failure.

One of the major questions with adult stem cell therapy is how do the stem cells go to where they are needed? Some people have made the argument that stem cells administered intravenously do not cause systemic effect because the majority get stuck in the lung and liver. Although cell sequestration is an issue, numerous studies have demonstrated therapeutic effects after intravenous administration of stem cells. Perhaps the most well-known stem cell homing molecule is stromal derived factor (SDF-1), which is made by injured and/or hypoxic tissue and causes stem cell mobilization and migration through activation of the CXCR4 receptor. The SDF-1/CXCR4 axis has been found in numerous conditions of tissue injury such as: stroke, heart attack, acoustic injured ear, liver failure, and post-transplant reconstitution of bone marrow. To understand how this “chemokine” works, the following video will describe it as relevant to stem cell repopulation post-irradiation: Homing of Stem Cells to Target Tissue

In a study published today scientists examined another signal made by injured tissue in order to assess whether it may act like SDF-1 and “call in” stem cells. The signal chosen was the amino acid adenosine, which is released from injured/necrotic cells. They found that adenosine did not by itself induce chemotaxis of mesenchymal stem cells (MSC) but dramatically inhibited MSC chemotaxis in response to the chemoattractant hepatocyte growth factor (HGF). Inhibition of HGF-induced chemotaxis by adenosine requires the A2a receptor and is mediated via up-regulation of the cyclic adenosine monophosphate (AMP)/protein kinase A pathway. Additionally, the investigators found that adenosine induces the expression of some key endodermal and hepatocyte-specific genes in mouse and human MSCs in vitro.

The ability of adenosine to modulate migration/differentiation processes implies that numerous paracrine/autocrine interactions are occurring during tissue injury. It will be critical to identify how to manipulate such factors to obtain maximal therapeutic responses.

Subsequent to the success of Mozobil, a small molecule chemical antagonist of CXCR4, several companies have been working at increasing the number of available means of mobilizing patient stem cells. One recent example is TaiGen Biotechnology Co., Ltd, which announced today the presentation of Phase I and preclinical data its CXCR4 antagonist TG-0054, at the ASH Annual Meeting held in New Orleans, the US, from December 5 to 8, 2009.

Date will be presented from a randomized, double-blind, placebo-controlled, sequential ascending single intravenous dose Phase I study. According to the press release, "TG-0054 exhibited excellent and favorable safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) profile."

The study was critical because it establishes a maximally tolerated dose that can be used for efficacy-finding Phase II clinical trials. One such trial, "A Phase II, Randomized, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics, and Hematopoietic Stem Cell Mobilization of TG-0054 in Patients with Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Disease" will begin to enroll patients in December, 2009.

Quite interestingly, the data presented will included details of the mechanism of mobilization, as well as the surprising finding that not only were hematopoietic (blood making) stem cells mobilized into circulation, but also stem cells for the blood vessels, called "circulating endothelial progenitor cells (EPC)."
The ability of TG-0054 to cause mobilization of EPC may support its use in other areas besides hematology. For example, it is known that patients with ischemic heart disease have low circulating EPC. By increasing the number of EPC, the body may be able to grow new blood vessels around the areas of ischemia, and thus inhibit progression, or even reverse the lack of oxygen to the myocardium.

To date, the classically used stem cell mobilizer, G-CSF, has been administered in patients with heart failure for increasing blood vessel production, as well as stimulation of endogenous regenerative mechanisms. Clinical trial results have been mixed, which may be due to other underlying factors associated with cardiac degeneration. By having an arsenal of several stem cell mobilizers, each having unique properties, future studies may be able to create a treatment protocol in which the patient is given drugs that activate stem cells, and the stem cells then home to the area where the body needs them.

Substantial progress has been made in the area of stem cells. Despite the Bush Administration’s 8 1/2 year ban on federal funding for embryonic stem cell research, and President Obama’s recent reversal, adult stem cell therapies have been making progress in terms of clinical implementation. This may be related to the safety concerns of embryonic stem cells, which have included differentiation into undesired tissues, as well as cancer. In contrast, adult stem cells have been used for more than 4 decades in the area of bone marrow transplantation and for over a decade in other areas. Primarily, non-bone marrow transplant studies have been focused in the area of heart failure, however smaller studies have investigated the use of stem cells in liver and kidney failure.

The field of stem cell therapies has recently been expanded. In a study published December 7in the medical journalPloS ONE, scientists from the University of California Los Angeles reported that human blood cells derived from adult stem cells can be engineered into cells that can target and kill HIV-infected cells – a process that could potentially be used against a range of chronic viral diseases.

The leader of the study, Dr. Scott G. Kitchen, Assistant Professor of Medicine in the Division of Hematology and Oncology at the David Geffen School of Medicine at UCLA and a Member of the UCLA AIDS Institute stated "We have demonstrated in this proof-of-principle study that this type of approach can be used to engineer the human immune system, particularly the T-cell response, to specifically target HIV-infected cells," Additionally, he commented on the possibility of future studies. "These studies lay the foundation for further therapeutic development that involves restoring damaged or defective immune responses toward a variety of viruses that cause chronic disease, or even different types of tumors."

Possible methods of manipulating blood cells to make them resistant to HIV infection includes genetically altering proteins called receptors. T cells have a specific receptor called CXCR5 which when mutated cannot be infected with HIV. Certain subsets of the human population who are resistant to HIV have this mutation in CXCR5, but also have normal T cell activities. One of the possible genetic alterations that can be performed in patients with HIV is to induce a similar CXCR5 mutation to endow resistance. Stem cell types that could be used include bone marrow, cord blood, or expanded peripheral blood stem cells.

Doctors at the University of Texas Medical School at Houston have announced initiation of an efficacy-finding study in the area of heart failure using a "universal donor" stem cell product called "Prochymal". This cell therapy drug is under development by the company Osiris Therapeutics and is the subject of substantial scientific interest internationally. Prochymal has made it to Phase III trials in the area of Graft Versus Host Disease, a side effect of bone marrow transplantation, however, data was not sufficiently strong to warrant FDA approval. Prochymal is made from the bone marrow mesenchymal stem cells of healthy human volunteers. It is a unique stem cell product in that it does not require matching with the recipient.

Data from Phase I clinical trial of Prochymal have been published in the Journal of the American College of Cardiology. The researchers involved in the Phase I trial reported that patients who received Prochymal intravenously after a heart attacked did not have adverse effects associated with the stem cell infusion. Therapeutic benefits were observed in the treated but not control patients, including reduction in number of arrhythmias, improved heart and lung function, and improvement in overall condition.

"We are able to use a stem cell product that is on the shelf without prior preparation of anything from the patient, and this product appears to be able to help the heart muscle recover after a heart attack," said Ali E. Denktas, M.D., the trial’s Houston site principal investigator and assistant professor of cardiology at the UT Medical School at Houston. "This means patients have the potential to recover quicker with less risk of an immediate secondary attack."

The first patient for the Phase II study at the Houston site was recruited today. The heart attack victim Melvin Dyess, 49, received an intravenous infusion of either the stem cells or placebo as part of the protocol of the double-blind study. The procedure took place at the Memorial Hermann Heart & Vascular Institute-Texas Medical Center. Denktas said UT Medical School researchers will continue to enroll willing patients into the Phase II study who are admitted to Memorial Hermann-Texas Medical Center. Neither patients nor their physicians know whether they received the stem cell drug.

The bone marrow is conventionally thought of as the location in the body where blood is made. Production of blood is regulated by the body’s needs and originates from a specialized type of stem cell called the “hematopoietic” stem cell.

There have been numerous studies demonstrating that the bone marrow also contains stem cells that are capable of regenerating injured heart tissue. Controversy exists as to which specific type of bone marrow stem cell is better at regenerating heart tissue, however the concept is not new. Back in 1999 researchers from the University of Toronto in Canada demonstrated that subsequent to induction of cardiac injury in laboratory rats, the injection of bone marrow stem cells that have been treated with a chemical agent (5-azacytidine) would cause significant recovery of the injury [1]. Treatment with the chemical agent resulted in cells that resembled heart cells in the test-tube, which were subsequently transplanted into the animal.

Later studies showed that for certain types of heart injury it was not necessary to treat the bone marrow stem cells with chemical agents, but that simple administration of these cells, either directly into the heart [2], or intravenously [3], was able to cause a therapeutic response.

Today at the American Heart Association’s Annual Meeting in Orlando Florida researchers from the University of Rostock presented data using stem cells from the bone marrow together with coronary artery bypass surgery in treating patients with heart failure due to poor circulation.

The researchers presented data on 10 patients that were administered a purified population of bone marrow stem cells. These stem cells were selected using a magnetic-based approach for expression of the protein CD133, which is associated with enhanced stem cell activity. The purpose was to increase circulation by causing formation of new blood vessels, as well as possibly increasing ability of the heart muscle to regenerate.

The study demonstrated efficacy in the treated patients based on increase cardiac muscle contraction ability as compared to patients that had bypass surgery but did not receive stem cells. However the number of subjects was too small to draw definitive conclusions. No treatment associated adverse effects were noted.

1. Tomita, S., et al., Autologous transplantation of bone marrow cells improves damaged heart function. Circulation, 1999. 100(19 Suppl): p. II247-56.

2. Barile, L., et al., Bone marrow-derived cells can acquire cardiac stem cells properties in damaged heart. J Cell Mol Med, 2009.

3. Krause, U., et al., Intravenous delivery of autologous mesenchymal stem cells limits infarct size and improves left ventricular function in the infarcted porcine heart. Stem Cells Dev, 2007. 16(1): p. 31-7.

There are several types of stem cell therapy that are in development. They can be broadly broken down into cells that come from the same patient, called autologous, and cells that derived from another source, called allogeneic. Autologous stem cells have the advantage not causing worries regarding immune rejection. Unfortunately, in many conditions that require stem cell therapy, such as peripheral artery disease, or coronary heart disease, the original stem cell pool in the patient is depleted. This is because on the one hand the body is constantly using the stem cells to try to heal itself, and on the other hand, there is an underlying inflammation in the conditions mentioned that suppress stem cell activity. Therefore, in some situations it is better to use "fresh" stem cells from another donor.

Mesenchymal stem cells can be extracted from bone marrow, fat, and several other sources. In contrast to the current dogma (which appears to be scientifically incorrect) that stem cells that make blood can not be transplanted without immune suppression, the current thinking for mesenchymal stem cells is that immune suppression is not needed when they are transplanted. Part of the reason for this is that mesenchymal stem cells have been published in many papers to actually "immune modulate". In other words, mesenchymal stem cells appear to have the ability to reprogram the immune system so as to not destroy them, but at the same time they allow the immune system to continue performing its usual function of destroying pathogens.

In a recent paper (Chin et al. Cryopreserved mesenchymal stromal cell treatment is safe and feasible for severe dilated ischemic cardiomyopathy. Cytotherapy. 2009 Nov 2) the use of mesenchymal stem cells was evaluated after the cells have been stored frozen. The importance of this is that an ideal stem cell treatment would be a "universal donor" stem cell "drug" in that cells could be shipped to the point of care frozen and used in the convenience of a doctor’s office, without the need for expensive equipment that is currently a requirement in the medical practice of stem cell therapy.

In the publication the scientists treated three patients with dilated cardiomyopathy with mesenchymal stem cells that were previously frozen. Stem cells were injected directly into the heart muscle as the patients were undergoing coronary artery bypass surgery. All three patients responded better than what would have been expected had they undergone surgery alone in terms of cardiac function, ejection volume, and reduction of scarring. Although the study was uncontrolled and therefore efficacy data is not solid, the fact that the procedure was performed safely, without adverse effects at 1-year follow-up suggests that more studies need to be performed to evaluate efficacy of this approach.

Cord blood is known to contain large numbers of stem cells. Currently, it is used as an alternative to bone marrow transplantation for certain conditions. Advantages of cord blood over bone marrow include the fact that it does not need to be as closely matched between donor and recipient as bone marrow does, and additionally, because the cord blood stem cells are younger, theoretically they should be more potent at re-establishing production of blood cells after a transplant.

In conventional cord blood transplants, which are usually performed for conditions such as leukemias, the immune system of the recipient is destroyed in order to allow the donor cord blood cells to engraft. Additionally, by providing large doses of chemotherapy, not only is the recipient immune system destroyed but many of the leukemic cells are also killed. The widespread use of cord blood in treatment of leukemias has led to a dogma being generated that cord blood transplants are useless when used for other treatments. Essentially, most hematologists believe that if a cord blood transplant is performed without prior treatment of the recipient with chemotherapy/immune suppressants, then one of two things will happen. The cord blood cells will either attack the recipient, a process called graft versus host disease, or conversely, the recipient immune system cells will destroy the cord blood cells, a process called host versus graft.

The current dogma, however, appears to be wrong. Firstly, cord blood administration has been performed in thousands of patients without adverse effects in absence of immune suppression. Why would someone administer cord blood for reasons besides stem cell transplants? Originally, cord blood was used as an alternative source of blood when adult blood shortages existed. The unique property of cord blood is that it contains fetal hemoglobin, which is much more effective at transporting oxygen than adult hemoglobin. Secondly, human cord blood has been used without suppression of the immune system in animal studies for conditions such as type I diabetes, ALS, and Parkinson’s Disease. The apparent ability of cord blood to induce therapeutic effects suggests that the cells were not rejected. Scientists at the Institute for Cellular Medicine have used cord blood derived cells in treatment of heart failure, which was described in a publication (Ichim et al. Placental mesenchymal and cord blood stem cell therapy for dilated cardiomyopathy. Reprod Biomed Online. 2008 Jun;16(6):898-905). The scientific rational for how cord blood stem cells may be administered without graft versus host or host versus graft reactions is provided in a paper written by the Institute for Cellular Medicine and Medistem, which is freely available at http://www.translational-medicine.com/content/5/1/8 .

A paper published today (Finney et al. Umbilical cord blood-selected CD133(+) cells exhibit vasculogenic functionality in vitro and in vivo. Cytotherapy. 2009 Nov 2.) from the Mary Laughlin’s group describes the use of cord blood cells in creation of new blood vessels. Several conditions would benefit from the creation of new blood vessels, for example, in diseases such as ischemic heart disease or peripheral artery disease, the body tries to make new blood vessels in order to compensate for occlusion in the existing blood vessels. Unfortunately, the body cannot make enough new blood vessels to keep up with demand. If cord blood stem cells could be used to make new blood vessels, this treatment would have numerous applications.

In the publication, the researchers describe that cord blood contains a higher number of cells expressing the CD133 marker. These are cells that on the one hand can make new blood cells (called hematopoietic stem cells), but have also been postulated by others to have the ability to generate the cells that line the blood vessels (endothelial cells).

By culturing purified cord blood CD133 cells with existing blood vessel cells outside of the body, the scientists found that the CD133 cells would increase the rate at which the blood vessel cells multiplied. Using this knowledge, the next question was whether the CD133 cells could stimulate formation of new blood vessels in animal models.

One of the major arteries that feeds the leg, called the femoral artery, was blocked in order to mimic conditions of decreased blood flow. Usually this results decreased function of the leg and death of muscle tissue. Administration of CD133 cells was shown to stimulate new blood vessel formation, preserve leg function, and decrease the amount of cell death in the digits of the mouse limbs. Activity of CD133 cells derived from cord blood seemed to be higher than that of bone marrow derived cells.

These studies suggest that cord blood derived stem cells may be therapeutically useful in conditions requiring formation of new blood vessels. In fact, a company called Medistem actually has filed patents on the use of drugs already approved for other indications in order to modify umbilical cord blood to increase potency in the stimulation of new blood vessels in patients with critical limb ischemia, an advanced form of peripheral artery disease.