Intravenous Bone Marrow For Stroke: Clinical Trial

Akihiko Taguchi from the Institute of Biomedical Research and Innovation in Kobe, Japan, in collaboration with a whole host of colleagues from various places treated stroke with their own bone marrow. This is a Phase 1/2 clinical trial but it is a very small trial that was neither blinded not placebo-controlled. Therefore, while this trial is useful, the results are of limited value.

In this clinical trial, 12 stroke patients were divided into two groups, one of which received 25 milliliters and the other of which received 50 milliliters of bone marrow cells 7-10 days after their strokes. The bone marrow cells were administered intravenously. To isolate bone marrow cells, the so-called “mononuclear fraction” was isolated from whole bone marrow samples that came from bone marrow aspirations. Patients were evaluated by means of brain imaging to measure blood flow in their brains, and a series of neurological tests. The National Institute of Health Stroke Scale or NIHSS scores were used to grade the neurological capabilities of each patient. Patients were examined 1 month and then 6 months after treatment.

All treated patients were compared with the records of other stroke patients in the past who were not treated with bone marrow cells. These comparisons showed that the bone marrow-treated patients showed a trend towards improved neurological outcomes. Statistically, the bone marrow-treated patients had significantly better blood flow and oxygen consumption in their brains 6 months after treatment compared to the historic controls. Also, the NIHSS scores of the bone marrow-treated patients were also significantly better than those of the historic controls. Patients who received the higher doses of bone marrow cells did better than those who received the lower doses.

There were also no apparent adverse effects to administering the bone marrow cells. One patient experienced pneumonia and sepsis 3 months after cell therapy, but data monitoring largely eliminated the cell therapy as being a contributing factor to this issue. Another patient experienced a seconded stroke that was detected the day after the cell therapy. Because the patient had shown signs of a stroke the day before treatment, the association between the cell therapy and the recurrent stroke is rather unclear. None of the other patients showed any worsening of their present strokes, seizures, or other complications.

All in aloe, it seems as though this procedure is safe, and there is a trend towards increased metabolic and neurological recovery. However, this is a very small study and these trends may not hold in a larger study. Secondly, these patients must be followed for an extended period of time in order to determine if these improvements are durable or transient. Finally, these improvements must be compared with a placebo if there are going to convince the FDA.

Bone marrow cells contain a variety of stem cells and other types of cells that may release cocktails of healing molecules that help cells survive, make new blood vessels, and tamp down inflammation. Additionally, bone marrow cells might stimulate resident populations of stem cells to proliferate and make new neurons and glial cells. Until these positive results can be reproduced in larger, better controlled studies, these results will remain interesting and hopeful, but ultimately inconclusive.

These results were published in Stem Cells and Development 2015 DOI: 10.1089/scd.2015.0160.

Remote Ischemic Conditioning Enhances Stem Cell Retention in the Heart

Stem cell administration to the heart after a heart attack is a difficult venture. Direct injection into the heart muscle is definitely the most sure-fire way to get stem cells into the heart tissue. However, direct injection requires that the physician crack the patient’s chest (thoracotomy), which is exquisitely unpleasant for the patient. Alternatively, there are devices that an deliver stem cell injections into the heart through the large veins in the legs, but these procedures require special equipment and lots of skills that your average cardiologist does not have. Another way is to administer stem cells through angioplasty. Using the same procedure as stent implantation, a delivery device is replaced at the site of heart damage through over-the-wire angioplasty technology, and the stem cells are delivered slowly and gradually through the coronary blood vessels. This does not require fancy equipment, and your average cardiologist could perform this technique pretty easily.

Problems exist with both procedures. Direct injection places cells and fluid into the heart wall and there is a risk of rupture. Likewise, with over-the-wire delivery of stem cells, there is the risk of clogging the coronary artery.

With both techniques, many stem cells end up in places other than the heart. In fact, the majority of the stem cells end up somewhere else – the lungs and liver mostly. Is there a better way?

Intravenous administration would be sweet, but that has been tried and the bottom line is that it bombed (Barbash et al., Circulation. 2003 19;108(7):863-8; Freyman et al., Eur Heart J. 2006 May;27(9):1114-22).

Well, some very enterprising scientists from China had an idea to get the intravenously administered stem cells to go to the heart and stay there. Bone marrow stem cells respond to a molecule called SDF1alpha (stromal cell derived factor-1alpha). On their cell surfaces, bone marrow cells have a receptor called CXCR4 which binds the SDF1alpha and bone marrow cells move towards higher and higher concentrations of SDF1alpha. Therefore, can you get the heart to make more SDF1alpha?

Sure. You can genetically engineer it to make more SDF1alpha. If you do that, the stem cells will pour out of the bone marrow and go to the heart and help fix it (Sundararaman S et al., Gene Ther. 2011 18(9):867-73). However, is there another way to get more SDF1alpha in the heart?

Yes there is. Let me introduce Remote Ischemic Conditioning or RIC. RIC increases the protection against injury that results from loss of blood flow to an organ. The way RIC works is that the blood supply to another organ is clamped so that this other organ is deprived of oxygen long enough to sound the alarm, but not long enough to do it serious damage. This deprivation of oxygen induces a flash of SDF1alpha production, which brings stem cells from bone marrow to the bloodstream and to the damaged organ.

Qin Jiang and colleagues from the Peking Union Medical College in Beijing, China used RIC in animals that had undergone a heart attack to determine if RIC could recruit more stem cells to the heart. Also, they administered bone marrow stem cells intravenously to see if RIC increased stem cell retention in the heart.

Jiang and others broke their laboratory rats into three groups (it gets a little complicated).

The first group was given heart attacks and then split into two subgroups. One subgroup received RIC and the second subgroup received surgery but no RIC.

The second group was given a heart attack and then split into six subgroups. Once subgroup was given RIC and intravenous bone marrow mesenchymal stem cells. the second received bone marrow mesenchymal stem cells by no RIC, only the incision, the third subgroup only received intravenous mesenchymal stem cells, the fourth group received RIC and intravenous saline, the fifth subgroup received no RIC, only an incision and intravenous saline, and the sixth subgroup received only intravenous saline.

The third group was given heart attacks and then split into two groups, one of which received RIC, intravenous mesenchymal stem cells and intravenous antibodies against CXCR4, and the other of which received RIC, mesenchymal stem cells and an antibody against nothing in particular.

The results showed that RIC GREATLY increased the amount of SDF1alpha in the heart. There was simply no getting around this. At 1 hour after RIC, SDF1alpha and VEGF (vascular endothelial growth factor) levels were up, but these levels decreased by 3 hours and back to normal by 6 hours after RIC.

Did these increased SDF1alpha levels increase stem cell retention? Oh yes!! The RIC-treated rats had almost twice the number of stem cells in their hearts than the animals that did not have RIC. Did this make a functional difference? Again, yes! The RIC-treated animals had hearts that functioned more normally (relatively speaking) than hearts from the non-RIC-treated animals.

The third experiment was even more informative, since the co-administration of the CXCR4 antibody abrogated the response induced by RIC. This demonstrates that effects of RIC are mediated by the SDF1alpha/CXCR4 axis and blocking this signaling axis prevented any benefits from RIC.

This paper is short, but very informative. It suggests that a relatively simple procedure like RIC could potentially improve the clinical efficacy of stem cell treatments. If this can be shown to work in larger animals, then clinical trials might be warranted. In fact clinical trials are presently underway in which SDF1alpha is being engineered into the heart to treat heart attack patients (see Hajjar RJ, Hulot JS. Circ Res. 2013 Mar 1;112(5):746-7).

Using Bone Marrow Stem Cells to Reprogram Neurons and Regenerate the Retina

Spanish researchers from the Center for Genomic Regulation (CGR) have regenerated the retina in mice by reprogramming neurons with bone marrow stem cells.

Cell reprogramming normally uses genetic engineering techniques that introduces genes into cells that push them into another cell fate without taking them through an embryonic-like state. One strategy for reprogramming cells fuses those cells with other cells that express genes that drive the fused cell into a different cell fate.

Pia Cosma and her team have used cell fusion to reprogram retinal neurons in mice. The mechanism consisted of introducing bone marrow stem cells into the damaged retina. The transplanted stem cells fused with existing retinal neurons, which conveyed to these retinal neurons the ability to regenerate the retina.

“For the first time we have managed to regenerate the retina and reprogram its neurons through in vivo cell fusion. We have identified a signaling pathway that, once activated, allows the neurons to be reprogrammed through their fusion with bone marrow cells,” said Pia Cosma, who is the head of the Reprogramming and Regeneration group at the CGR and ICREA (Institució Catalana de Recerca i Estudis Avançats) research professor.

Daniela Sanges, first author or the work and postdoctoral researcher in Pia Cosma’s laboratory, said, “This discovery is important not only because of the possible medical applications for retinal regeneration but also for the possible regeneration of other nervous tissues.”

The study demonstrates that the regeneration of nervous tissue by means of cell fusion is possible in mammals and describes this new technique as a potential mechanism for the regeneration of more complex nervous tissue.

This research is in the very early stages but already there are laboratories interested in being able to continue the work and take it to a more applied level.

Daniela Sanges, Neus Romo, Giacoma Simonte, Umberto Di Vicino, Ariadna Diaz Tahoces, Eduardo Fernández, Maria Pia Cosma. Wnt/β-Catenin Signaling Triggers Neuron Reprogramming and Regeneration in the Mouse Retina . Cell Reports – 25 July 2013 (Vol. 4, Issue 2, pp. 271-286)

Bioengineered Trachea Implanted into a Child

Hannah Genevieve Warren was born in 2010 in Seoul, South Korea with tracheal agenesis, which is to say that she was born without a trachea. Hannah had a tube inserted through her esophagus to her lungs that allowed her to breathe. Children with tracheal agenesis usually die in early childhood, 100% of the time. No child with this condition has ever lived past six years of life. Hannah spent the first two years of her life at the Seoul National Hospital before she was transported to Illinois for an unusual surgery.

While at the Children’s Hospital of Illinois, on April 9, 2013, Hannah had a bioengineered trachea transplanted into her body. This trachea was the result of a remarkable feat of technology called the InBreath tracheal scaffold and bioreactor system that was designed and manufactured by Harvard Bioscience, Inc. Harvard Bioscience, or HBIO, is a global developer, manufacturer and marketer of a broad range of specialized products, primarily apparatus and scientific instruments, used to advance life science research and regenerative medicine.

InBreath tracheal scaffold
InBreath tracheal scaffold

Hannah’s tracheal transplant was the first regenerated trachea transplant surgery that used a biomaterial scaffold that manufactured by the Harvard Apparatus Regenerative Technology (HART) Inc., a wholly owned subsidiary of Harvard Bioscience. HART ensured that the scaffold and bioreactor were custom-made to Hannah’s dimensions. Then the scaffold was seeded with bone marrow cells taken from Hannah’s bone marrow, and the cells were incubated in the bioreactor for two days prior to implantation. Because Hannah’s own cells were used, her body accepted the transplant without the need for immunosuppressive (anti-rejection) drugs.

InBreath Bioreactor
InBreath Bioreactor

The surgeons who participated in this landmark transplant were led by Dr. Paolo Macchiarini of Karolinska University Hospital and Karolinska Institutet in Huddinge, Stockholm and Drs. Mark J. Holterman and Richard Pearl both of Children’s Hospital of Illinois. This surgery was approved by the FDA under an Investigational New Drug (IND) application submitted by Dr. Holterman.

Dr. Mark Holterman, Professor of Surgery and Pediatrics at University of Illinois College of Medicine at Peoria, commented: “The success of this pediatric tracheal implantation would have been impossible without the Harvard Bioscience contribution. Their team of engineers applied their talent and experience to solve the difficult technical challenge of applying regenerative medicine principles in a small child.”

David Green, President of Harvard Bioscience, said: “We would like to congratulate Dr. Macchiarini, Dr. Holterman, Dr. Pearl and their colleagues for accomplishing the world’s first transplant of a regenerated trachea in a child using a synthetic scaffold and giving Hannah a chance at a normal life. We also wish Hannah a full recovery and extend our best wishes to her family.”

Hannah’s surgery is the seventh successful implant of a regenerated trachea in a human using HART technology. Prior successes included the first ever successful regenerated trachea transplant in 2008, the first successful regenerated trachea transplant using a synthetic scaffold in 2011, and the commencement of the first clinical trial of regenerated tracheas in 2012. HART has plans to commence discussions with the FDA and EU regulatory authorities in the near future regarding the clinical pathway necessary to bring this new therapeutic approach to a wider range of patients who are in need of a trachea transplant.

Scientists Remove Extra Chromosome 21 from the Cells of Down Syndrome Patient

University of Washington researchers have done something seemingly impossible: they have removed the extra copy of chromosome 21 in cells taken from a patient with Down syndrome. This gene therapy technique targets only the extra genetic material in the cell, and scientists were able to successfully remove the extra chromosome 21 without damaging the integrity of the rest of the chromosomes present in the nucleus.

The first reaction to this news is to shout, “there’s a cure for Down Syndrome!” Unfortunately that is not the case. However, it might be a way to treat Down Syndrome patients who have blood cancers. Down syndrome patients are at increased risk for leukemia, and this technique, pioneered by Dr. David Russell and his colleagues is meant to fix the errant bone marrow cells in culture and then reintroduce the fixed cells back into the patient.

Dr. Russell explained: “We are certainly not proposing that the method we describe would lead to a treatment for Down syndrome. What we are looking at is the possibility that medical scientists could create cell therapies for some of the blood-forming disorders that accompany Down syndrome.” Dr. Russell is from the University of Washington’s Department of Medicine.

This technique works on cultured cells grown in a laboratory. The cells are infected with an engineered virus that inserts into the extra chromosome. Then the cells are grown under conditions that kill all cells with the viral DNA. Only those cells that spontaneously lose the extra copy of chromosome 21 survive the culture conditions.

This protocol could potentially treat Down syndrome patients with leukemia with genetically-modified stem cells that are derived from their own cells, but lack the extra chromosome. Stem cells could be taken from the bone marrow of the patients, the doctors could remove the extra chromosome, and then the healthy cells could then be grown and transplanted back into the bone marrow of the patient. This same technique could also be used for leukemia patients whose bone marrow cells have an extra chromosome, but do not have Down syndrome.

This is great news for those with Down syndrome and for all those who live with any kind of trisomy. Also, since gene therapy can introduce new defects into the patient’s DNA, this technique could potentially remove unwanted extra bits of DNA without adversely affecting other chromosomes. This is certainly a major achievement.

Protecting Blood Cell-Making Stem Cells from Cancer Drugs and Radiation

Our bone marrow serves as the nursery for blood cells. All the circulating blood cells, red cells, white cells and platelets, are derived from a rare population of bone marrow cells known as hematopoietic stem cells or HSCs. Normally, the majority of HSCs rest and take a break while a small fraction of them proliferates and differentiates into progenitor cells that differentiate into mature red and white blood cells.

When the body needs more blood cells, for example after blood loss or during inflammation, more HSCs proliferate. However, what tells a HSC to cool it and take a powder or wake up get up and get dividing remains mysterious. Nevertheless, we do know one thing: location, location, location. Within the bone marrow are specialized site called “niches” that direct the behavior of the HSC. Quiescent niches, for example, house resting HSCs but other niches, known as vascular niches, are located in close proximity to the blood vessels that line the bone marrow sinusoids and harbor the minority of hard-working HSCs.

A new paper in Nature Medicine by Ingrid Winkler from the Mater Medical Research Institute and various other collaborators has clarified one of the mechanisms that tell HSCs to keep proliferating. A cell adhesion molecule called E-selectin is expressed by some bone marrow blood vessel cells (endothelial cells) in those blood vessels close to that thin layer of connective tissue that lines that the medullary cavity (endosteum).

E-selectin is normally expressed in endothelial cells that are experiencing inflammation. Inflammation is the result of tissue damage, and inflammation induces the synthesis E-selectin in endothelial cells. When white blood cells sense that damage has occurred that they are needed to fight off invading microorganisms, they bind to inflamed endothelial cells and crawl between them. Selectins, in general bind to sugar residues on the surfaces of cells, and are, therefore, members of a larger group of sugar-binding proteins known as lectins.

Back to the bone marrow: When mice that genetically lacked E-selectin were examined, they had fewer proliferating HSCs in their bone marrow. Was this due to problems with their HSCs? Clearly not, because when the HSCs from the E-selectin-deficient mice were transferred into normal mice, they divided perfectly well, and when normal HSCs were dropped into the bone marrow the E-selectin-deficient mice, they also failed to proliferate very much. The difference in these mice is their bone marrow microenvironments and not their stem cells.

HSCs divided less in E-selectin-deficient mice, but when normal mice were treated mice small molecules that inhibited E-selectin aged slower and also were protected against toxic stress-inducing conditions such as radiation and chemotherapeutic drugs. Inhibition of E-selectin inhibition improved mouse survival and recovery after radiation and chemotherapy.

As you might guess, E-selectin inhibitors are already in clinical trials for sickle-cell disease. This might very well accelerate the translation of these data such as these to the clinic. Just think, treating patients with E-selectin inhibitors before radiation or chemotherapy might protect the quiescent HSCs from the toxic effects of cancer therapeutics. Also, treatment that induces HSC quiescence also reduces leukocyte production, and could also elicit anti-inflammatory effects by reducing the systemic supply of leukocytes. These data from Winkler’s paper might be the impetus for designing ways to protect patients from the side effects of cancer therapy.

See I. G. Winkler et al., Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med., published online 21 October 2012 (10.1038/nm.2969).

Bone Marrow Stem Cells Can Create Cell Types Specfic to Heart, Brain, and Other Tissues

A collaboration between researchers at the University of Paris Decartes and the University of Maryland School of Medicine has used bone marrow stem cells to generate cell types from many different tissues such as the heart, brain and pancreas. This scientific breakthrough might lead to potential new ways to replace cells lost during injury, disease, infection or trauma.

Lead researcher David Trisler, a developmental neurobiologist at the University of Maryland School of Medicine, said: “Finding stem cells capable of restoring function to different damaged organs would be the Holy Grail of tissue engineering, This research takes us another step in that process by identifying the potential of these adult bone marrow cells, or a subset of them known as CD34+ bone marrow cells, to be ‘multipotent,’ meaning they could transform and function as the normal cells in several different organs.”

Trisler’s group at the University of Maryland have previously developed a special culturing system to collect a select sample of adult stem cells from bone marrow (Goolsby, et al., PNAS 2003 100(25): 14926-31). Bone marrow normally houses stem cells that make all red and white blood cells. However, there are also immature stem cells in the bone marrow that have a greater ability to differentiate. Trisler’s groups found bone marrow stem cells that express genes specific to the nervous system and also cells that express genes from embryonic tissues (Pessac, et al., C R Biol. 2011 334(4):300-6). For this project, Trisler’s team used an animal model similar to the one used to prove the multipotency of embryonic stem cells in order to demonstrate that these immature bone marrow stem cells could make more than just blood cells.

In this procedure, researchers injected the isolated stem cells into mouse embryos, and then the injected cells were then traced as the embryo developed to determine which cell types the stem cells made. Investigators found that the bone marrow stem cells (CD34+ cells) had a limited lifespan and did not produce teratomas, which are the tumors that sometimes form with the use of embryonic stem cells and adult stem cells cultivated from methods that require genetic manipulation.

Paul Fishman, M.D., Ph.D., professor of neurology, said: “When taken at an early stage, we found that the CD34+ cells exhibited similar multipotent capabilities as embryonic stem cells, which have been shown to be the most flexible and versatile. Because these CD34+ cells already exist in normal bone marrow, they offer a vast source for potential cell replacement therapy, particularly because they come from a person’s own body, eliminating the need to suppress the immune system, which is sometimes required when using adults stem cells derived from other sources”

Proving the potential of adult bone marrow stem cells opens new possibilities for scientific exploration, but more research is needed to see how this science can be translated to humans and clinical treatments.

The FOCUS-CCTRN Trial – Transendocardial Delivery of Bone Marrow Stem Cells Improves Heart Function in Heart Attack Patients

Mayo Clinic researchers have completes a Phase II clinical study that demonstrates that bone marrow stem cells can fix a sick heart. They discovered that stem cells derived the bone marrow of heart patients, when isolated and injected into their hearts, improved heart function. These researchers also found that particular types of the stem cells seemed to be responsible for the largest patient improvement, and, therefore, warrant further study.

This clinical study is an extension of earlier work in Brazil that treated a small number of patients with fewer stem cells (Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107(18):2294-2302.). The earlier study treated 21 patients, seven of whom received placebo treatments and fourteen others who received injections of bone marrow stem cells into the walls of their hearts.  In this study, a total of 92 (82 men; average age: 63 years) were randomly assigned to the placebo or experimental groups (n=61 in Bone Marrow Cell transplant group and n=31 in the placebo group).  This patient group suffered from coronary artery disease or LV dysfunction, and limiting heart failure or angina.  These patients had weakened hearts as a result of previous heart attacks.

These 92 patients received either a placebo (sterile saline bereft of any cells) or 100 million bone marrow-derived stem cells that were extracted from the patient’s hips. In all cases the treatment consisted of a one-time injection into the wall of the heart.  This injection procedure actually consisted of 15 small injections in stem cells into regions of the ventricle wall that were known to consist of live cells as demonstrated by previous “electromechanical mapping” studies of the heart (see Willerson JT, Perin EC, Ellis SG, et al. Intramyocardial injection of autologous bone marrow mononuclear
cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]). Am Heart J. 2010;160(2):215-223
for a description of this mapping).  The injections were made performed with a NOGA catheter.  This clinical trial is the first clinical to use such a large a dose of stem cells.

NOGA Catheter

The significance of using these patient’s own bone marrow stem cells is not lost on cardiologists, since previous reports have shown that bone marrow from patients with chronic heart conditions or who have suffered heart attacks show diminished stem cell populations and activities (see Heeschen C, Lehmann R, Honold J, et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004;109(13):1615-1622 & Kissel CK, Lehmann R, Assmus B, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49(24):2341-2349).  If higher doses of stem cells can still help improve the function of such heart patients, then perhaps such a protocol would be helpful for them.

Mayo Clinic cardiologist Robert Simari, who was part of this study, said “We found that the bone marrow cells did not have a significant impact on the original end points that we chose, which involved reversibility of a lack of blood supply to the heart, the volume of the left ventricle of the heart at the end of a contraction, and maximal oxygen consumption derived through a treadmill test.” Simari is chairman of the Cardiovascular Cell Therapy Research Network (CCTRN), which is a network of five academic centers and associated satellite sites that conducted the study. The CCTRN is supported by the National Heart, Lung, and Blood Institute, which also funded the study.

Simari described the results of this study: “But interestingly, we did find that the very simple measure of ejection fraction was improved in the group that received the cells compared to the placebo group by 2.7 percent.” Ejection fraction refers to the average percentage of blood pumped from the left ventricle each time the heart pumps.  You can listen to Simari discuss this clinical trial here.

Emerson Perin, and James Willerson of the Texas Heart Institute, who were the principal investigators in this study, noted that although 2.7 percent does not seem like a large number, it does represent a statistically significant increase and this means an improvement in heart function for chronic heart failure patients who have no other options.

Dr. Perin noted, “This was a pretty sick population. They had already had heart attacks, undergone bypass surgery, and had stents placed. However, they weren’t at the level of needing a heart transplant yet. In some patients, particularly those who were younger or whose bone marrows were enriched in certain stem cell populations had even greater improvements in their ejection fractions.”

The study participants had an average age of 63 years old, but this study showed that those patients who are younger than the average participant age improved more than the average. In these patients, the ejection fraction improved by 4.7 percent. The variable that seemed to predict whether or not the patient would benefit from this procedure was the quality of their bone marrow stem cells.  Detailed examinations of bone marrow stem cell populations from each patient showed that younger patients who showed greater improvements have large quantities of CD34+- and CD133+-type stem cells in their bone marrow isolates.  Stem cells with these particular markers tend to produce blood vessels and making more blood vessels, increases the flow of oxygen and nutrients to the heart muscle.  This spares the damaged heart muscle from experiencing more damage and shores the existing heart muscle to improve its function.

Dr. Simari concluded, “This tells us that the approach we used to deliver the stems cells was safe. It also suggests new directions for the next series of clinical trials, including the type of patients, endpoints to study and types of cells to deliver.”

Polish Study Shows Stable Improvements Two Years After Heart Stem Cell Transplant

Stem cell treatments for heart attacks can improve heart function after a heart attack. This has been repeated shown in laboratory animals and human trials have also established the efficacy of bone marrow-based heart treatments. Despite these successes, there are some indications that the improvements wrought by bone marrow stem cell transplants into the heart are not stable, and the functional increases caused by it are transient.

To determine is functional improvements in the heart are transient or stable, Jaroslaw Kaspzak and his colleagues at the Medical University of Lodz, Poland have published a study in which they treated 60 heart attack patients and then tracked them for two years. Their study was published in the journal Kardiologia Polska, which, fortunately, is in English, since I do not read Polish.

In this study, 60 heart attack patients were treated with primary angioplasty and randomly assigned to two groups. The first group consisted of 40 patients who were treated with standard care, and bone marrow stem cell transplants.  The bone marrow cells were harvested 3-11 days after the heart attack. The bone marrow cells were administered to the heart by means of intracoronary catheters (over the wire balloon catheter) very near to the area of the infarct (the area in the heart damaged by the heart attack).  The second group of 20 patients were treated with standard care.  All patients were subjected to echocardiography before treatment and 1, 3, 6, 12, and 24 months after treatment.  Additionally, the percentages of patients who experienced subsequent heart attacks, admission to the hospital for heart failure, or revascularization, was tabulated two years after the treatment.

Just after the heart attack, the heart function of both groups was essentially the same.  The fraction of blood pumped from the heart (ejection fraction) in the treated group was 35% ± 6% and 33% ± 7% in the control group (normal is 55% – 70%).  The volume of blood left in the heart after it contracts (end systolic volume) was 95 milliliters ± 39 milliliters in the treated group and 99 milliliters ± 49 milliliters in the control group (normal is 50-60 milliliters).  The amount of blood in the heart after it fills (end diastolic volume) was 149 ± 48 milliliters in the treated group and 151 ± 65 milliliters in the control group (normal is 120-130 milliliters).  The end diastolic volume  (EDV) is a measure of the firmness of the heart walls.  A damaged heart is not as firm and its flaccid walls expand greatly and take up more volume, which puts further strain upon the heart.  Thus a DECREASE in the EDV is an indication of improvement in the heart.  Nevertheless, it is clear that before the treatment regimes were instigated, the average medical conditions of the two groups was essentially the same, at least when it comes to the heart.

The results of each treatment strategy are rather telling. The ejection fraction in the control group increased 3.7% one moth after the heart attack, 4.7% by 6 months, 4.8% at 12 months, and 4.7% at 24 months.  This this group saw its greatest increase six months after the heart attack and although this increase was stable, it was modest at best.  The bone marrow-treated group, however, saw an average ejection fraction increase of 7.1% after one month, 9.3% at 6 months, 11.0% after one year, and 10% after two years.  Thus the bone marrow-treated group not only showed a much faster and more robust increase in injection fraction, but an increase that was sustained two years after the procedure.  Also, the treated group saw half the percentage of deaths due to cardiac events (5%) than that observed in the control group (10%).  The percentage of hospitalizations for heart failure in the treated group (3%) was 20% of that seen in the control group (15%).  The rates of revasculaizations and new heart attacks was essentially the same in both groups.

This study joins other long-term studies that have demonstrated long-term improvements in heart attack patients treated with heart infusions with bone marrow-derived stem cells.  The REPAIR-AMI clinical trial, which examined 204 heart attack patients, showed stable, long-term benefits that lasted for at least two years for those patients who had been treated with infusions of bone marrow stem cells.  Other studies have not found no significant differences between heart attack patients treated with standard care and those who also received bone marrow infusions.  However, there are probable explanations for many of these failures.  The ASTAMI study that failed to show significant differences between the two groups not only transplanted a lower number of cells than this present study and the successful REPAIR-AMI study.  Secondly, the negative FINCELL study used patients whose average ejection fractions were 59% ± 11%.  Clinical studies that have tested bone marrow heart infusions have established that those patients with lower ejection fractions are helped the most by them.  This is the case of the negative HEBE study; the patients with the lowest ejection fraction showed the greatest improvements relative to the control group, but these improvements were swamped out by those with higher ejection fractions that were not helped nearly as much.  Third, the meta-analysis of Martin-Rendon showed that the best time period to treat heart attack patients was 4-7 days after the heart attack.  In the HEBE study, patients received bone marrow infusions 7 days after angioplasty.  How soon after the heart attack was the angioplasty performed?  This is not reported, probably because it varied from patient to patient.  Nevertheless, this places the treatment outside the optimum established by other experiments.

Thus, once again, we see that bone marrow treatments for hearts are safe, and effective, and they convey long-term benefits to patients who receive them.  Much work remains, since only some people consistently benefit from these treatments.  Why is this the case?  Only more work will tell.

Bone Marrow Stem Cells Differentiate into Brain-Specific Cell Types in Laboratory Animals

Spanish researchers have observed the ability of bone marrow-derived stem cells (BMDC) to contribute to a several different neural cell types in other areas of the brain besides the cerebellum, including the olfactory bulb, because of a mechanism of “plasticity”. BMDCs have been recognized as a source for transplantation because they have the capacity to contribute to different cell populations in several different organs under both normal and pathological conditions. Many BMDC studies have aimed at repairing damaged brain tissue or helping to restore lost neural function, and much of that research has focused on BMDC transplants to the cerebellum, which is located at the back of the brain.

Eduardo Weruaga of the University of Salamanca, Spain commented, “To our knowledge, ours is the first work reporting the BMDC’s contribution to the olfactory neurons, We have shown for the first time how BMDCs contribute to the central nervous system in different ways in the same animal depending on the region and cell-specific factors.”

Weruaga and his group grafted bone marrow cells into mutant mice that suffered from degeneration of specific neuronal populations at different ages. Then they compared these mice to similarly transplanted healthy controls, and they found that increased numbers of transplanted BMDCs did increase the number of bone marrow-derived stem cells in the experimental groups. However, six weeks after transplantation, more bone marrow-derived microglial cells were observed in the olfactory bulbs of the test animals even though degeneration of mitral cells was still in progress. Such a difference was not observed in the cerebellum where cell degeneration had been completed.

Weruaga noted: “Our findings demonstrate that the degree of neurodegenerative environment can foster the recruitment of neural elements derived from bone marrow. But we also have provided the first evidence that BMDCs can contribute simultaneously to different encephalic areas through different mechanisms of plasticity: cell fusion for Purkinje cells, which are among the largest and most elaborately dendritic neurons in the human brain, and differentiation for olfactory bulb interneurons.”

The Salamanca group also confirmed that BMDCs fuse with Purkinje cells in the cerebellum, but they also found that the neurodegenerative environment had no effect on the behavior of the BMDCs. “Interestingly, the contribution of BMDCs occurred through these two different plasticity mechanisms, which strongly suggests that plasticity mechanisms may be modulated by region and cell type-specific factors,” he said.

Paul R. Sanberg, distinguished professor of Neuroscience at the Center of Excellence for Aging and Brain Repair, University of South Florida made this observation about Weruaga’s study: “This study shows a potential new contribution of bone marrow derived cells following transplantation into the brain, making these cells highly versatile, in their ability to both differentiate into and fuse with endogenous neurons.” Bone marrow stem cells continue to surprise researchers with their plasticity and ability to become other cell types.