Abu Zubair meriwayatkan dari Jabir bin Abdullah bahwa Nabi Muhammad SAW bersabda:

"Setiap penyakit ada obatnya. Jika obat yang tepat diberikan dengan izin Allah, penyakit itu akan sembuh".

(HR. Muslim, Ahmad dan Hakim).

Rabu, 30 Desember 2009

Stem Cells for Heart Muscle Cells

Stem Cell Therapy: Helping the Body Heal Itself
Stem cells are nature’s own transformers. When the body is injured, stem cells travel the scene of the accident. There, they help heal damaged tissue. They do this by transforming themselves into whatever type of cell has been injured. Stem cells can become bone, skin – even heart tissue. When your heart muscle is damaged in a heart attack, stem cells are summoned from the bone marrow to make repairs. Stem cells do a good job. But they could do better – for some reason, the heart stops signaling for heart cells after only a week or so after the damage has occurred, leaving the repair job mostly undone. The partially repaired tissue becomes a burden to the heart, forcing it to work harder and less efficiently, leading to heart failure.

Researchers believe that we can we can boost the efficiency of stem cells and help the body recover faster and better from heart attacks, even after the heart has stopped signaling for them. They’ve developed methods to enhance the body’s natural repair function, both in the setting of heart attack and congestive heart failure. Now these methods are being tested in clinical trials. Some of them are enrolling patients now. If you’re interested, read about some of these clinical trials below.
Clinical trials using stems cells to heal the heart:

ATHERSYS MULTISTEM: Following an acute myocardial infarction (AMI), the body automatically recruits stem cells from the bone marrow to repair damaged heart tissue. The problem, however, is the molecular signals that recruit the new stem cells stay on for only a short period. Consequently, damage to the myocardium is never repaired, which weakens its functionality and leads to chronic heart failure.

Cleveland Clinic also enrolled the first AMI patient who was treated with a multipotent adult progenitor cell developed by Cleveland-based biotech firm Athersys Inc. The first cohort of the Phase I clinical trial thus far suggests the Athersys MultiStem cell was administered safely and was well tolerated by the patients. This Phase I trial is continuing to recruit patients.

In preclinical AMI models, MultiStem has shown the potential to improve heart function. The MultiStem cells are derived from bone marrow of qualified donors.

“MultiStem is being developed as an off-the-shelf product so that it can be administered in the catheterization lab at any hospital while the patient is undergoing a stent procedure to open the artery,” says Marc S. Penn, MD, PhD, Department of Stem Cell Biology and Regenerative Medicine and the Robert and Suzanne Tomsich Department of Cardiovascular Medicine. “A Cricket Micro-Infusion Catheter, a proprietary device developed by Mercator Med Systems, enables physicians to rapidly and efficiently deliver the MultiStem cells in to the damaged region of the heart.”

Cleveland Clinic’s Department of Stem Cell Biology and Regenerative Medicine also is a key clinical site for national stem cell trials currently recruiting patients including trials being run by the National Institutes of Health Cardiovascular Cell Therapy Research Network. They include:

IMPACT-DCM: Led at Cleveland Clinic by Nicholas Smedira, MD, Cardiothoracic Surgery, this Phase II trial will examine intramyocardial delivery of autologous bone marrow cells in ischemic and non-ischemic patients with chronic heart failure due to dilated cardiomyopathy (DCM). Patients randomized into the treatment group of the IMPACT-DCM trial are treated with Cardiac Repair Cells (CRCs), an autologous, mixed-cell product (Aastrom Biosciences) containing expanded populations of stem and early progenitor cells produced from a small sample of the patient’s own bone marrow. The CRCs are injected into the heart muscle through minimally invasive surgery. The IMPACT-DCM trial will determine the safety and tolerability of CRCs compared to standard-of-care in patients with DCM.

MARVEL: This Phase II/III trial will assess safety and efficacy of MyoCell (Bioheart) autologous clinical cell therapy into myocardium post myocardial infarction to determine if adult stem cells can improve heart function. After autologous myoblasts are harvested from a patient’s skeletal muscle tissue, they are isolated and expanded in culture in a closed system. When a sufficient number of cells are estimated, they are taken from culture, packaged in a suspension and injected directly into the myocardium via the femoral artery.

TIME: The trial, led by site PI Stephen G. Ellis, MD, Cardiovascular Medicine, will provide stem cell infusions to patients three days or seven days after they receive percutaneous coronary intervention (PCI) for AMI. The study will evaluate the safety and effectiveness of placing bone marrow derived stem cells into the myocardium to improve its function following an AMI after successful revascularization. What’s more, the study will help determine the best time to deliver the stem cells after MI.

Late TIME: Also led by Dr. Ellis, this trial is similar to the TIME study. The only difference is that patients will receive their own bone marrow derived stem cells two to three weeks following AMI and PCI. For some patients, delaying the delivery of stem cells two to three weeks after AMI may be better than initiating treatment during the acute phase.

FOCUS: This trial will assess the effectiveness of bone marrow derived stem cell treatment for adults with chronic heart failure due to a history of myocardial infarction. Some patients with this condition, especially those with substantial scar tissue on the myocardium’s wall, or patients with a particular heart structure, may not be eligible to receive standard treatments of coronary artery bypass grafting or coronary angioplasty and stent placement. The trial, led by Dr. Ellis, will evaluate whether bone marrow derived stem cells may be an effective way to achieve therapeutic angiogenesis and improvement in heart function.

Coming Soon in 2010:
In January 2010, Dr. Penn expects to launch a new Phase I clinical trial to determine the safety and efficacy of stromal derived factor-1 (SDF-1) proprietary technology developed by Cleveland Clinic. In preclinical studies, animals that were injected with genes that express SDF-1 protein showed definite improvement in cardiac function over those animals that were given control genes.

Dr. Penn says the goal of this new gene therapy is to stimulate the recruitment of the patient’s own stem cells to repair the damaged heart tissue and to induce angiogenesis (new blood vessel growth). This trial is rather unique because most research involves harvesting stem cells from patients and delivering them directly into the heart via minimally invasive procedures and specially designed catheters.

Dr. Ellis, Dr. Penn, Dr. Smedira and their colleagues in the Heart & Vascular Institute are working hard to bring these developing stem cell therapies to the patient's bedside in a safe and timely fashion.
Important information about stem cell trials:
All stem cell studies have strict protocols, approved by the FDA and the Cleveland Clinic Institutional Review Board for inclusion and exclusion criteria. To insure you meet the criteria, patients need to be evaluated by a physician and may require specific testing at the Cleveland Clinic. This testing may take more than one day to complete if you require studies or consultations with multiple physicians.
Stem cell trials are randomized controlled studies – not all patients who undergo evaluation for stem cell trials will receive stem cell therapy.
Each study has different protocols and the stem cells are accessed and administered differently, and have different criteria for follow-up. The research team will discuss all aspects of the trial with you in detail prior to signing consent and participating in the trial.
Patients are not given monetary compensation for testing to determine enrollment into the different studies. Once a patient meets the screening baseline criteria and informed consent has been reviewed and signed, patients are not charged for any therapy or monitoring that is directly related to the research. Travel, lodging and meals are not covered by the studies.

Cleveland Clinic is a large referral center for advanced heart disease and heart failure – we offer a wide range of therapies – including medications, devices and surgery. Patients will be evaluated for the treatments that best address their condition. Whether patients meet the criteria for stem cell therapy – or not, they will be offered the most advanced array of treatment options.


Adult Stem Cells Repair Heart Attack Damage
Adult stem cells may help repair heart tissue damaged by heart attack according to the findings of a new study to be published in the December 8 issue of the Journal of the American College of Cardiology. Results from the Phase I study show stem cells from donor bone marrow appear to help heart attack patients recover better by growing new blood vessels to bring more oxygen to the heart.

Rush University Medical Center was the only Illinois site and one of 10 cardiac centers across the country that participated in the 53-patient, double-blind, placebo-controlled Phase I trial. Rush is now currently enrolling patients for the second phase of the study.

Researchers say it is the strongest evidence thus far indicating that adult stem cells can actually differentiate, or turn into heart cells to repair damage. Until now, it has been believed that only embryonic stem cells could differentiate into heart or other organ cells.

"The results point to a promising new treatment for heart attack patients that could reduce mortality and lessen the need for heart transplants," said Dr. Gary Schaer, head of the Rush Cardiac Catheterization Laboratory and study principal investigator at Rush.

In phase I of the study, a group of 53 patients who had heart attacks in the previous ten days received adult mesenchymal stem cells and were kept under close study for two years.

The mesenchymal stem cells (MSC) were harvested from the bone marrow of healthy adult donors. These cells have the potential to develop into mature heart cells and new blood vessels. Similar to Blood Type O, mescenchymal stem cells have the advantage that they can be taken from the bone marrow of an unrelated donor without needing to be matched by blood type.

After the stem cells were extracted, they were purified by drug manufacturer Osiris Therapeutics into a formulation for intravenous delivery called Prochymal. Patients were administered an infusion of either Prochymal or placebo as an injection into a vein in the arm or leg. To prevent bias, neither the patient nor the physician knew who received the stem cell treatment and who received the placebo.

In the study, patients who received the adult stem cells were compared to similar patients who received inert placebo injections. Both were followed by MRI and echocardiogram.

After six months, patients who received the adult stem cells were four times as likely to have improved overall condition, were able to pump more blood with each heartbeat than untreated patients, had only one-quarter as many dangerous heart arrhythmias, and suffered no toxicity or other serious adverse side effects from the treatment.

"It is suspected that these stem cells may take part in the growth of new blood vessels to bring more oxygen to the heart and help reduce the scarring from a heart attack," said Schaer.

Echocardiograms showed patients had improved heart function, particularly in those patients with large amounts of cardiac damage. Patients also have improvements in lung function.

According to Schaer, one reason the study results are so promising is that these stem cells can be used without tissue typing and do not trigger an immune response, and are available for every patient.

A unique benefit of the stem cell product is that it is given to patients through a standard intravenous (IV) line which is simple and easy for the patient compared to other therapies that require delivery to the site of the disease through catheterization or open surgical procedures,

Adult stem cells are designed by nature to perform tissue repair in a mature adult. It is believed that these cells can be used in patients unrelated to the donor, without rejection, eliminating the need for donor matching and recipient immune suppression. Once transplanted, the cells promote healing of damaged or diseased tissues.

"It is possible that in the future, hospitals might be able to keep frozen adult stem cells on hand for speedy use in treating heart attacks," said Schaer.

"This study suggests that adult bone marrow derived stem cells are more flexible than previously thought," said Schaer. "If the benefits and safety are confirmed in the oingoing Phase II trial, we may soon have a remarkable new therapy for patients with a large heart."

Rush is currently seeking participants for the second phase of the study.

About Rush University Medical Center
Rush University Medical Center is an academic medical center that encompasses the more than 600 staffed-bed hospital (including Rush Children's Hospital), the Johnston R. Bowman Health Center and Rush University. Rush University, with more than 1,270 students, is home to one of the first medical schools in the Midwest, and one of the nation's top-ranked nursing colleges. Rush University also offers graduate programs in allied health and the basic sciences. Rush is noted for bringing together clinical care and research to address major health problems, including arthritis and orthopedic disorders, cancer, heart disease, mental illness, neurological disorders and diseases associated with aging.

Source: Rush University Medical Center

Stem Cells Repair Heart Attack Damage
'Off-the-Shelf' Stem Cell Product Safe, May Mend Hearts
By Daniel J. DeNoon
WebMD Health News
Reviewed by Louise Chang, MD

Dec. 1, 2009 -- Can stem cells safely repair heart attack damage? Yes, a clinical trial suggests.

Bone marrow stem cells are supposed to home in on damaged parts of the heart. Once there, they send out signals that help the body repair the injury. There's also evidence, from animal studies, that the stem cells themselves engraft to the heart and help repopulate dead cells with new, living cells.

Now there's evidence from actual patients who suffered heart attacks. It comes from a study led by cardiologist Joshua M. Hare, director of the stem cell institute at the University of Miami Miller School of Medicine, and colleagues at nine other medical centers.

"Stem cell-treated patients had ... significant improvements in heart, lung, and global function,” Hare said in a news release. "Echocardiography showed improved heart function, particularly in those patients with large amounts of cardiac damage."

It's not the first time heart attack patients have been treated with stem cells. But previous studies used bone marrow cells extracted from the patient and then injected directly into the heart.

Hare's team used an "off-the-shelf" stem cell product -- Prochymal -- containing stem cells harvested from a single healthy donor and grown to large numbers in laboratories. Prochymal is given by intravenous infusion. It's made by Osiris Therapeutics Inc., which sponsored the study, and which currently seeks FDA approval of the product as a treatment for graft-versus-host disease in transplant recipients.

"Many have argued that it’s premature to test stem cells in patients," Hare said. "This trial ... lays the foundation for a brand new cell-based therapy for the human heart."

The Hare study enrolled 53 heart attack patients treated within 10 days of their first heart attack. None of the patients required bypass. A fourth of the patients got infusions of an inactive placebo; the others got various doses of the Prochymal cells.

The main goal of the study was to see if Prochymal was safe. It had been feared that the cells might cause growth of unwanted tissue in the arteries or the lungs; this did not happen. Patients receiving the stem cells had fewer adverse events than those who received placebo.

The secondary goal of the study was to gather some evidence that the treatment actually helped. There was such evidence -- particularly in the patients with the largest infarcts (patches of heart tissue killed during a heart attack).

Why? Emergency signals sent out by wounded heart tissue attract help from stem cells. It's probable that the stronger signal from the more damaged hearts attracted more of the stem cells to the site of injury, suggest Cleveland Clinic researchers Marc S. Penn, MD, PhD, and colleagues in an editorial accompanying the Hare report in the Dec. 8 issue of the Journal of the American College of Cardiology.

Warning that the Hare study is only a first step, Penn and colleagues call the findings "important."

"Many questions remain, but there is excitement in what the future holds with regard to advances in this field," they write.

A phase 2 clinical trial, also sponsored by Osiris, is enrolling heart attack patients.


Can Stem Cells Repair a Damaged?
Heart attacks and congestive heart failure remain among the Nation's most prominent health challenges despite many breakthroughs in cardiovascular medicine. In fact, despite successful approaches to prevent or limit cardiovascular disease, the restoration of function to the damaged heart remains a formidable challenge. Recent research is providing early evidence that adult and embryonic stem cells may be able to replace damaged heart muscle cells and establish new blood vessels to supply them. Discussed here are some of the recent discoveries that feature stem cell replacement and muscle regeneration strategies for repairing the damaged heart.

For those suffering from common, but deadly, heart diseases, stem cell biology represents a new medical frontier. Researchers are working toward using stem cells to replace damaged heart cells and literally restore cardiac function.

Today in the United States, congestive heart failure—the ineffective pumping of the heart caused by the loss or dysfunction of heart muscle cells—afflicts 4.8 million people, with 400,000 new cases each year. One of the major contributors to the development of this condition is a heart attack, known medically as a myocardial infarction, which occurs in nearly 1.1 million Americans each year. It is easy to recognize that impairments of the heart and circulatory system represent a major cause of death and disability in the United States [5].

What leads to these devastating effects? The destruction of heart muscle cells, known as cardiomyocytes, can be the result of hypertension, chronic insufficiency in the blood supply to the heart muscle caused by coronary artery disease, or a heart attack, the sudden closing of a blood vessel supplying oxygen to the heart. Despite advances in surgical procedures, mechanical assistance devices, drug therapy, and organ transplantation, more than half of patients with congestive heart failure die within five years of initial diagnosis. Research has shown that therapies such as clot-busting medications can reestablish blood flow to the damaged regions of the heart and limit the death of cardiomyocytes. Researchers are now exploring ways to save additional lives by using replacement cells for dead or impaired cells so that the weakened heart muscle can regain its pumping power.

How might stem cells play a part in repairing the heart? To answer this question, researchers are building their knowledge base about how stem cells are directed to become specialized cells. One important type of cell that can be developed is the cardiomyocyte, the heart muscle cell that contracts to eject the blood out of the heart's main pumping chamber (the ventricle). Two other cell types are important to a properly functioning heart are the vascular endothelial cell, which forms the inner lining of new blood vessels, and the smooth muscle cell, which forms the wall of blood vessels. The heart has a large demand for blood flow, and these specialized cells are important for developing a new network of arteries to bring nutrients and oxygen to the cardiomyocytes after a heart has been damaged. The potential capability of both embryonic and adult stem cells to develop into these cells types in the damaged heart is now being explored as part of a strategy to restore heart function to people who have had heart attacks or have congestive heart failure. It is important that work with stem cells is not confused with recent reports that human cardiac myocytes may undergo cell division after myocardial infarction [1]. This work suggests that injured heart cells can shift from a quiescent state into active cell division. This is not different from the ability of a host of other cells in the body that begin to divide after injury. There is still no evidence that there are true stem cells in the heart which can proliferate and differentiate.

Researchers now know that under highly specific growth conditions in laboratory culture dishes, stem cells can be coaxed into developing as new cardiomyocytes and vascular endothelial cells. Scientists are interested in exploiting this ability to provide replacement tissue for the damaged heart. This approach has immense advantages over heart transplant, particularly in light of the paucity of donor hearts available to meet current transplantation needs.

What is the evidence that such an approach to restoring cardiac function might work? In the research laboratory, investigators often use a mouse or rat model of a heart attack to study new therapies (see Figure 9.1. Rodent Model of Myocardial Infarction). To create a heart attack in a mouse or rat, a ligature is placed around a major blood vessel serving the heart muscle, thereby depriving the cardiomyocytes of their oxygen and nutrient supplies. During the past year, researchers using such models have made several key discoveries that kindled interest in the application of adult stem cells to heart muscle repair in animal models of heart disease.

Recently, Orlic and colleagues [9] reported on an experimental application of hematopoietic stem cells for the regeneration of the tissues in the heart. In this study, a heart attack was induced in mice by tying off a major blood vessel, the left main coronary artery. Through the identification of unique cellular surface markers, the investigators then isolated a select group of adult primitive bone marrow cells with a high capacity to develop into cells of multiple types. When injected into the damaged wall of the ventricle, these cells led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells, thus generating de novo myocardium, including coronary arteries, arterioles, and capillaries. The newly formed myocardium occupied 68 percent of the damaged portion of the ventricle nine days after the bone marrow cells were transplanted, in effect replacing the dead myocardium with living, functioning tissue. The researchers found that mice that received the transplanted cells survived in greater numbers than mice with heart attacks that did not receive the mouse stem cells. Follow-up experiments are now being conducted to extend the posttransplantation analysis time to determine the longer-range effects of such therapy [8]. The partial repair of the damaged heart muscle suggests that the transplanted mouse hematopoietic stem cells responded to signals in the environment near the injured myocardium. The cells migrated to the damaged region of the ventricle, where they multiplied and became "specialized" cells that appeared to be cardiomyocytes.

A second study, by Jackson et al. [3], demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow. In this model, investigators purified a "side population" of hematopoietic stem cells from a genetically altered mouse strain. These cells were then transplanted into the marrow of lethally irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack via the tying off of a different major heart blood vessel, the left anterior descending (LAD) coronary artery. At two to four weeks after the induced cardiac injury, the survival rate was 26 percent. As with the study by Orlic et al., analysis of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells. Thus, the mouse hematopoietic stem cells transplanted into the bone marrow had responded to signals in the injured heart, migrated to the border region of the damaged area, and differentiated into several types of tissue needed for cardiac repair. This study suggests that mouse hematopoietic stem cells may be delivered to the heart through bone marrow transplantation as well as through direct injection into the cardiac tissue, thus providing another possible therapeutic strategy for regenerating injured cardiac tissue.

More evidence for potential stem cell-based therapies for heart disease is provided by a study that showed that human adult stem cells taken from the bone marrow are capable of giving rise to vascular endothelial cells when transplanted into rats [6]. As in the Jackson study, these researchers induced a heart attack by tying off the LAD coronary artery. They took great care to identify a population of human hematopoietic stem cells that give rise to new blood vessels. These stem cells demonstrate plasticity meaning that they become cell types that they would not normally be. The cells were used to form new blood vessels in the damaged area of the rats' hearts and to encourage proliferation of preexisting vasculature following the experimental heart attack.

Like the mouse stem cells, these human hematopoietic stem cells can be induced under the appropriate culture conditions to differentiate into numerous tissue types, including cardiac muscle [10] (see Figure 9.2. Heart Muscle Repair with Adult Stem Cells). When injected into the bloodstream leading to the damaged rat heart, these cells prevented the death of hypertrophied or thickened but otherwise viable myocardial cells and reduced progressive formation of collagen fibers and scars. Control rats that underwent surgery with an intact LAD coronary artery, as well as LAD-ligated rats injected with saline or control cells, did not demonstrate an increase in the number of blood vessels. Furthermore, the hematopoietic cells could be identified on the basis of highly specific cell markers that differentiate them from cardiomyocyte precursor cells, enabling the cells to be used alone or in conjunction with myocyte-regeneration strategies or pharmacological therapies. (For more about stem cell markers see Appendix E.i. How Do Researchers Use Markers to Identify Stem Cells?)

Exciting new advances in cardiomyocyte regeneration are being made in human embryonic stem cell research. Because of their ability to differentiate into any cell type in the adult body, embryonic stem cells are another possible source population for cardiac-repair cells. The first step in this application was taken by Itskovitz-Eldor et al. [2] who demonstrated that human embryonic stem cells can reproducibly differentiate in culture into embryoid bodies made up of cell types from the body's three embryonic germ layers. Among the various cell types noted were cells that had the physical appearance of cardiomyocytes, showed cellular markers consistent with heart cells, and demonstrated contractile activity similar to cardiomyocytes when observed under the microscope.

In a continuation of this early work, Kehat et al. [4] displayed structural and functional properties of early stage cardiomyocytes in the cells that develop from the embryoid bodies. The cells that have spontaneously contracting activity are positively identified by using markers with antibodies to myosin heavy chain, alpha-actinin, desmin, antinaturietic protein, and cardiac troponin—all proteins found in heart tissue. These investigators have done genetic analysis of these cells and found that the transcription-factor genes expressed are consistent with early stage cardiomyocytes. Electrical recordings from these cells, changes in calcium-ion movement within the cells, and contractile responsiveness to catecholamine hormone stimulation by the cells were similar to the recordings, changes, and responsiveness seen in early cardiomyocytes observed during mammalian development. A next step in this research is to see whether the experimental evidence of improvement in outcome from heart attack in rodents can be reproduced using embryonic stem cells.

These breakthrough discoveries in rodent models present new opportunities for using stem cells to repair damaged heart muscle. The results of the studies discussed above are growing evidence that adult stem cells may develop into more cell types than first thought. In those studies, hematopoietic stem cells appear to be able to develop not only into blood, but also into cardiac muscle and endothelial tissue. This capacity of adult stem cells, increasingly referred to as "plasticity," may make such adult stem cells a viable candidate for heart repair. But this evidence is not complete; the mouse hematopoietic stem cell populations that give rise to these replacement cells are not homogenous. Rather, they are enriched for the cells of interest through specific and selective stimulating factors that promote cell growth. Thus, the originating cell population for these injected cells has not been identified, and the possibility exists for inclusion of other cell populations that could cause the recipient to reject the transplanted cells. This is a major issue to contend with in clinical applications, but it is not as relevant in the experimental models described here because the rodents have been bred to be genetically similar.

What are the implications for extending the research on differentiated growth of replacement tissues for damaged hearts? There are some practical aspects of producing a sufficient number of cells for clinical application. The repair of one damaged human heart would likely require millions of cells. The unique capacity for embryonic stem cells to replicate in culture may give them an advantage over adult stem cells by providing large numbers of replacement cells in tissue culture for transplantation purposes. Given the current state of the science, it is unclear how adult stem cells could be used to generate sufficient heart muscle outside the body to meet patients' demand [7].

Although there is much excitement because researchers now know that adult and embryonic stem cells can repair damaged heart tissue, many questions remain to be answered before clinical applications can be made. For example, how long will the replacement cells continue to function? Do the rodent research models accurately reflect human heart conditions and transplantation responses? Do these new replacement cardiomyocytes derived from stem cells have the electrical-signal-conducting capabilities of native cardiac muscle cells?

Stem cells may well serve as the foundation upon which a future form of "cellular therapy" is constructed. In the current animal models, the time between the injury to the heart and the application of stem cells affects the degree to which regeneration takes place, and this has real implications for the patient who is rushed unprepared to the emergency room in the wake of a heart attack. In the future, could the patient's cells be harvested and expanded for use in an efficient manner? Alternatively, can at-risk patients donate their cells in advance, thus minimizing the preparation necessary for the cells' administration? Moreover, can these stem cells be genetically "programmed" to migrate directly to the site of injury and to synthesize immediately the heart proteins necessary for the regeneration process? Investigators are currently using stem cells from all sources to address these questions, thus providing a promising future for therapies for repairing or replacing the damaged heart and addressing the Nation's leading causes of death.


Scientists find master heart cell
Harvard discovery gives new tools for drug development
By Carolyn Y. Johnson

Harvard University scientists said yesterday they discovered a master human heart cell that gives rise to three major types of heart tissue, providing new tools for drug development and an important advance toward the ultimate goal of repairing damaged hearts.
Using human embryonic stem cells, the researchers have unraveled part of the process by which the human heart is built during development - insight they hope could be used to understand congenital heart disease and create new therapies for cardiovascular disease, the top cause of death in the United States.

“Since these [cells] are entirely human, you can use this system now to study the role of specific genes in human heart disease, and as ways to screen drugs for cardiotoxicity and for therapeutic effect,’’ said Dr. Kenneth R. Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital and principal faculty member at the Harvard Stem Cell Institute. He is senior author of the paper, published in Nature yesterday.

The work points to new applications for regenerative medicine. For years, attempts to repair damaged heart tissue using different types of cells have come back with “ambiguous, disappointing, marginal, and, in certain cases, negative’’ results, Chien said. For example, Genzyme Corp. of Cambridge stopped enrolling patients in a clinical trial for a heart cell therapy three years ago because it was deemed to have little chance of success.

Because the new work reveals progenitor cells that naturally create specific types of heart tissue during development, Chien thinks they might have a better chance of repairing damaged hearts.

But the greatest near-term promise of the work might be in routine drug development. It could now be possible, for example, to create large numbers of heart muscle cells to test drugs.

“Add one drug, two drugs, or all combinations of drugs a heart patient would take’’ to test how effective or toxic compounds are in actual human heart cells, said Christine Mummery, a professor of developmental biology at Leiden University Medical Center who was not involved with the work. “It’s really a kind of tool to bring us a step further.’’

Drug companies are especially interested in such applications. Using the actual human cells affected by a disease, instead of mice, dogs, or other stand-ins, could potentially speed up drug development by giving com panies a more accurate template for screening potential drugs. Animal cells and other types of assays have been invaluable for testing and screening drugs, but the new cells could give scientists a chance to see how the human cells they are interested in react to drugs.

Such cells could also prevent companies from spending too much time on a drug that ultimately fails. One big concern at pharmaceutical companies is that drugs might have a side effect on the heart that only emerges late in the drug development process, said John D. McNeish, executive director of Pfizer Regenerative Medicine. Testing the drug on human heart cells might alert scientists to side effects before they begin administering the drug to patients in clinical trials.


Stem Cells From Skin Cells Can Make Beating Heart Muscle Cells
ScienceDaily (Feb. 13, 2009) — A little more than a year after University of Wisconsin-Madison scientists showed they could turn skin cells back into stem cells, they have pulsating proof that these "induced" stem cells can indeed form the specialized cells that make up heart muscle.

In a study published online Feb. 12 in Circulation Research, UW-Madison School of Medicine and Public Health professor of medicine Tim Kamp and his research team showed that they were able to grow working heart-muscle cells (cardiomyocytes) from induced pluripotent stem cells, known as iPS cells.

The heart cells were originally reprogrammed from human skin cells by James Thomson and Junying Yu, two of Kamp's co-authors on the study.

"It's an encouraging result because it shows that those cells will be useful for research and may someday be useful in therapy,'' said Kamp, who is also a cardiologist with UW Health. "If you have a heart failure patient who is in dire straits — and there are never enough donor hearts for transplantation — we may be able to make heart cells from the patient's skin cells, and use them to repair heart muscle. That's pretty exciting."

It's also a few more discoveries away. The researchers used a virus to insert four transcription factors into the genes of the skin cell, reprogramming it back to an embryo-like state. Because the virus is taken up by the new cell, there is a possibility it eventually could cause cancer, so therapies from reprogrammed skin cells will likely have to wait until new methods are perfected.

Still, the iPS cardiomyocytes should prove immediately useful for research. And Kamp said the speed at which knowledge is progressing is very encouraging.

Jianhua Zhang, lead author on the study, noted that it took 17 years, from when a mouse embryonic stem cells were first created in 1981, to 1998, when Thomson created the first human embryonic stem cells. In contrast, the first mouse iPS stem cells were created in 2006, and Thomson and Yu published their paper in November 2007, announcing the creation of human iPS stem cells that began as a skin cells.

While research on embryonic stem cells is controversial, because it destroys a human embryo, lessons learned through such research apply to current work with iPS cells made from adult cells.

"That's one of the important things that have come out of the research with embryonic stem cells, it taught us how human pluripotent stem cells behave and how to work with them,'' Kamp says. "Things are able to progress much more quickly thanks to all the research already done with embryonic stem cells."

Many types of heart disease have known genetic causes, so creating cardiomyocytes grown from patients who have those diseases will likely be some of the next steps in the research. One of Kamp's colleagues, Clive Svendsen, a UW-Madison School of Medicine and Public Health professor of neurology and anatomy, has grown the iPS cells into disease-specific neural cells. Kamp and Svendsen are also on the faculty of the Waisman Center and the Stem Cell and Regenerative Medicine Center.

Kamp's latest research, proving that iPS cells can become functional heart cells, is just one step along the way to better understanding and treatment of disease.

"We're excited about it, because it's the some of the first research to show it can be done, but in the future, we'll probably say, 'Well, of course it can be done,'" he says. "But you don't know until you do it. It's a very mysterious and complicated dance to get these cells to go from skin cells to stem cells to heart cells."


Scientists have moved a step closer to creating functioning heart tissue for transplants in the lab.
They have grown three types of human heart cells from cultures derived from embryonic stem cells.

When a mix of the cells was transplanted into mice with simulated heart disease, the animals' heart function was significantly improved.

The study, by a team of Canadian, US and UK scientists, features in the journal Nature.
In the future, these cells may be very effective in developing new strategies for repairing damaged hearts.

Dr Gordon Keller
McEwen Centre for Regenerative Medicine

The researchers created the cells by supplying embryonic stem cell cultures with a cocktail of growth factors and other molecules involved in development.

By supplying the right growth factors at the right time, they encouraged the cells to grow into immature versions of three different types of cardiac cell.

The three cell types they created - cardiomyocytes, endothelial cells and vascular smooth muscle cells - are each important constituents of heart muscle.

Researcher Dr Gordon Keller, from the McEwen Centre for Regenerative Medicine in Toronto, said: "This development means that we can efficiently and accurately make different types of human heart cells for use in both basic and clinical research.

"The immediate impact of this is significant as we now have an unlimited supply of these cells to study how they develop, how they function and how they respond to different drugs.

"In the future, these cells may also be very effective in developing new strategies for repairing damaged hearts, following a heart attack."

Jeremy Pearson, associate medical director at the British Heart Foundation, said: "This research provides another promising indication that we are steadily getting closer to the day when stem cells will be used successfully to repair damaged hearts in patients."


From stem cells to heart muscle
'This moves us closer to heart stem cell therapy'
A team of Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital (MGH) and collaborators at Harvard’s School of Engineering and Applied Sciences (SEAS) has taken a giant step toward the possibility of using human stem cells to repair damaged hearts.

The researchers, led by HSCI principal faculty member Kenneth Chien, report using a mouse version of a human cardiac master stem cell to create a functioning strip of mouse heart muscle with technology developed by Kevin Kit Parker, the Thomas Dudley Cabot Associate Professor of Applied Science in Harvard’s School of Engineering and Applied Sciences and a faculty member at the University’s Wyss Institute for Biologically Inspired Engineering.

“This is the beginning of making heart parts for heart disease,” said Chien, the director of the MGH Cardiovascular Research Center and the Charles Addison and Elizabeth Ann Sanders Professor of Basic Science at Harvard Medical School (HMS).

The new work by the HSCI-SEAS team, being published in tomorrow’s edition of the journal Science, raises the possibility of someday using induced pluripotent stem cell (iPS) technology to take a skin cell from a patient with heart disease to use in generating muscle tissue to repair the diseased heart — avoiding the need to suppress the immune system and the possibility of rejection, a major issue in organ transplantation.

“This is an initial step in moving beyond heart stem cell biology towards a different level — finding a rare cardiomyogenic cell from embryonic stem cells that can proliferate on its own and could potentially be therapeutic. This work moves us closer to heart stem cell therapy,” Chien explained. “The beauty of the system our team has developed relates to the almost pure population of the exact cells, ventricular heart cells, which we’re trying to replace in a damaged heart, and then expanding and assembling them into a functioning strip of pure ventricular muscle. That has not been done to my knowledge.”

We’ve “been able to take these very rare populations of muscle progenitors that were isolated because we were able to color code the cells,” Chien continued. “We look for the cells that have a mixed-color read out. We’ve been able to take those cells and put them one layer thick on something that is almost like saran wrap. When they contract, they flex the film. We have the pure cells; they can be expanded, and they can make a fully functional strip of muscle.”

Parker, whose lab developed the technology that produces a strip of muscle from the cardiac cells, said, “We try to develop technologies that are cell-agnostic — technologies that can work with Ken’s cardiac progenitors, or anyone else’s stem cells. These techniques are not limited to cardiac cells, or even to stem cells for that matter.”

The bioengineer explained that the best way to visualize the construction of the muscle strip might be to think of a “Fruit Roll-up,” but with cells taking the place of the pressed fruit.

Chien called the new findings “the latest in a chain of scientific discoveries that have come out of our lab here at Mass General and the Harvard Stem Cell Institute that have been a collaboration of physicians, scientists and bioengineers. For the first time we report the identification of a cell that could be viewed as perhaps an optimal cell type to promote cardiac muscle regeneration because the cells that we use come from embryonic stem cells and then have been induced to form an intact strip of functioning ventricular muscle.” Chien said the work takes the most basic form of undifferentiated stem cell and directs its differentiation and development “to ventricular muscle — and that’s the type of muscle in the heart we’re trying to regenerate.”

“What we think we have right now are the exact cell types to do this type of repair,” said Ibrahim Domian, first author on the Science paper and an HMS instructor in medicine. “One way or another we have to get to three-dimensional muscle, which is made up of multiple layers of cells. The amazing thing about these strips we have now is that they are generating the right amount of force, but as you want to generate more force, you have to increase the thickness of the strips, and they have to have their own blood supply. There are two ways you could do this; rely on tissue engineering to produce a strip like that, or find a way to use the natural architecture of the heart to regenerate the muscle. We’re now working hard in our lab, and with Kit Parker, to see how we could produce the thicker strip.”

There are a number of approaches to solving the delivery problem, Chien said. One might be to incorporate the cells into a gel of some kind, which could be applied to the damaged muscle. Another might be to simply inject the cells into the damaged tissue, hoping that they would proliferate and create new muscle. In Chien’s view, novel technology for cell delivery will be required in either case.

Over the past two years Chien and his team have published a series of “leap-frogging” studies, first making a discovery in mice, then replicating it in human embryonic stem cells, then taking the next step in mice, then moving on to human cells. Next comes the attempt to actually repair cardiac damage in animals and then on to clinical studies in the next five years.

“In mice we’re in a position to attempt the repair right now,” Domian said. “We can cause a heart attack, and then look for ways to repair the tissue. The simplest way is to inject the cells into the tissue – we can do that right now in a mouse. If that doesn’t work, we have to rely on other technologies.” But, he added, “this is direct proof of concept that a similar approach will work” with human embryonic stem cells.

“Now we’re actually in the core of the next level of challenges that face all of regenerative medicine,” said Chien. “In essence, I think we’re moving quite quickly now from stem cell biology all the way through towards regenerative medicine.”


Human stem cells fix heart damage in lab rats
By Carol M. Ostrom
Seattle Times health reporter

Human embryonic stem cells have been used to regrow the heart muscles of rats that had survived lab-induced heart attacks, scientists from the University of Washington and a private biotechnology company reported Sunday.

Because the rebuilt heart muscle halted the progression of heart failure, the findings offer encouragement that treatments based on embryonic stem cells someday might be used to help people who suffer heart attacks, a leading cause of death in the U.S., said Chuck Murry, a UW researcher and an author of the study.

Unlike many tissues in the body, heart muscle cells don't regenerate. So when heart attacks cause heart cells to die, they are replaced by scar tissue, which doesn't beat. Often, that leads to outright heart failure and death.

Murry, director of the Center for Cardiovascular Biology at the UW's Institute for Stem Cell and Regenerative Medicine, has long struggled to use adult stem cells to re-create heart muscle. He and UW colleague Michael Laflamme, the lead researcher on this study, knew from other studies that human embryonic stem cells could become heart muscle cells in rats — an encouraging first step.

But in practice, only a tiny percentage of the stem cells were actually becoming heart-muscle cells. And most died quickly after being injected into rats' hearts.

After four years of research, Murry and his colleagues at Geron, a biotechnology company in Menlo Park, Calif., had a breakthrough: They found a process to coax as many as half the cells into becoming heart-muscle cells, and second, a way to keep the cells alive.

Not only did all the rats start getting new heart muscle, but they were protected from the progression of heart failure, Murry said.

"No one had ever grown human heart muscle back in an injured animal," Murry said. "We're pretty pleased."

The research is published in the September issue of Nature Biotechnology.

Like most research in this area, Murry's is incremental, building on his own previous findings and those of other researchers.

Funding for this study came partially from Geron, which hopes to develop medical products to help heart-attack survivors. Other funding came from the federal National Institutes of Health.

"There's an epidemic of heart failure coming on as baby boomers age," Murry said.

Stem cells are promising to researchers because they have the ability to turn into any kind of cell in the body. The challenge has been finding ways to control their transformations.

So for Murry and his colleagues, the problem was to get the cells to become heart-muscle cells instead of cells for livers, kidneys or something else. At first, they had little success, but then found certain proteins would trigger the right growth.

When they put the cells into damaged hearts, however, the cells died en masse.

"Almost everything we put in died," Murry said. "It's a very harsh environment. It's what killed the heart muscle cells to begin with, so maybe it's not surprising that it killed those cells."

The researchers tried one intervention after another. "We were trying to be very scientific, trying one approach at a time, but nothing worked," Murry said.

Finally, they hit on a "pro-survival cocktail" of chemicals and also applied heat to the cells to make them behave. "Lo and behold, in 100 percent of the animals we delivered the cells to, we saw grafts," Murry said.

About 10 percent of a damaged heart area was restored, enough to stop the progression of the heart failure.

That came as a surprise, Murry said. "The fact that if you can grow human heart muscle back, that prevents heart failure — we didn't know that."

The study, which ran for four weeks, didn't reveal what would have happened in the long run to the rats that got the stem cells.

To make the breakthrough, Murry and his colleagues used the so-called "presidential lines" of stem cells. Those cells are generated from a group of embryos that already had been destroyed before the Bush administration limited research on embryonic stem cells.

"We're pleased to be able to provide an example of something that can be done with embryonic cells that can't be done with adult stem cells," Murry said.

Murry hopes someday to work with newer lines that would be more suitable for human transplantation.


Stem cell treatment of Cardiovascular diseases
Heart Disease
Coronary heart disease (CHD) is a narrowing of the small blood vessels that supply blood and oxygen to the heart. CHD is also called coronary artery disease (CAD). Angina (chest pain) is the most common symptom of CHD. Other common symptoms include shortness of breath and fatigue with activity.

Heart Failure is a life-threatening condition in which the heart can no longer pump enough blood throughout the body. Cardiomyopathy, (weakening of the heart muscle or a change in its structure) is often associated with heart failure.

Standard treatments for CHD and heart failure are diet control, medications and surgical procedures such as stenting to open up clogged arteries or coronary artery bypass grafting (CABG) to build detours around clogged portions of the arteries.
The XCell-Center Heart Treatment

The XCell-Center's heart treatment differs from standard methods because it is a drug-free alternative focused on repairing heart muscle and increasing blood flow within the heart muscle itself.

The entire procedure requires patients to stay in Germany for 4 or 5 nights.
Bone Marrow Collection

On the first day, bone marrow is collected from the patient's iliac crest (hip bone) using thin-needle mini-puncture under local anesthesia. Although some pain is felt when the needle is inserted, most patients do not find the bone marrow collection procedure particularly painful. The entire procedure normally takes about 30 minutes.

Once the bone marrow collection is complete, patients may return to their hotel and go about normal activities.

More detailed information on the bone marrow collection procedure is available in the Bone Marrow Informed Consent document (PDF file).
Laboratory Processing

The next day, the stem cells are processed from the bone marrow in a state-of-the-art, government approved (cGMP) laboratory. In the lab, both the quantity and quality of the stem cells are measured. These cells have the potential to transform into multiple types of cells and are capable of regenerating or repairing damaged heart tissue.

Stem Cell Implantation
On the third day, the stem cells are implanted back into the patient by angiography under local anesthesia. A special catheter (thin hollow wire) is inserted into the femoral artery and then guided forward under x-ray scanning until it reaches the targeted areas where the stem cells are then injected. During this procedure, additional treatments such as coronary artery stenting can be performed if necessary. The angiography procedure takes about 90 minutes.

Once all the cells have been successfully implanted, patients stay at the hospital overnight for monitoring and to allow the catheter entry point to close properly. They may return home after being released from the hospital the following day.
Patient Stories

Aaron Wood, Age 60 - 3 heart attacks and heart failure
"I no longer have any angina pain or no shortness of breath - no symptoms whatsoever. I am walking 3 miles per day and lifting heavy weights again. I consider this a complete reversal. I saw my cardiologist 2 weeks ago for more testing and he is still shaking his head!"

The price of the heart angiography treatment is 11,500 Euros.

Evaluation Process
To begin the treatment evaluation process, you must complete an online medical history form. Once you've completed the online medical history and submitted it, a patient relations consultant will contact you within 3 business days. He or she will assist you with the rest of the evaluation process. Upon treatment approval, your consultant will also assist you with treatment scheduling and trip preparation.

If you will be in Germany, you may also schedule an in-person consultation/evaluation with an XCell-Center physician. You may also request a "fast-track" evaluation and treatment schedule.


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