StemCell Therapy

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Stem cells tested for heart attack repair

LAGUNA HILLS, Calif., May 29, 2012 /PRNewswire/ --LoneStar Heart Inc., today announced the advancement of a new therapeutic strategy aimed at genetic reprogramming of cardiac fibroblasts into functioning heart muscle cells to treat damage following a heart attack and other forms of heart disease. The announcement follows a study conducted by researchers at the University of Texas Southwestern Medical Center (UT Southwestern), published in the on-line May 13th issue of the journal Nature, demonstrating feasibility of the approach. The company has acquired exclusive worldwide rights to the new technology.

The adult human heart has almost no regenerative capacity. Instead of rebuilding muscle tissue after a heart attack, or myocardial infarction, the injured human heart forms fibrous, non-contractile scar tissue lacking muscle or blood vessels. Fibroblasts account for a majority of cells in the heart and are activated following injury to form this fibrotic scar tissue. Fibrosis impedes regeneration of cardiac muscle cells, and contributes to loss of contractile function, ultimately leading to heart failure and death. Therapeutic strategies to promote new muscle formation, while limiting fibrosis, represent an attractive approach for heart repair.

As reported in Nature, Eric N. Olson, Ph.D., and colleagues from UT Southwestern show that four gene-regulatory proteins GATA4, HAND2, MEF2C, and TBX5 (GHMT) can convert cardiac fibroblasts into beating cardiac-like muscle cells. Introduction of these proteins into proliferating fibroblasts in mice reprograms them into functional cardiac-like myocytes, improving cardiac function and reducing fibrosis and adverse remodeling of the heart following myocardial infarction. Using cell lineage-tracing techniques, the investigators conclude that newly formed cardiac-like muscle cells in GHMT-treated hearts arose from pre-existing cardiac fibroblasts. Cardiac imaging studies confirmed the new technique promoted a dramatic increase in cardiac function that was sustained for at least three months following myocardial infarction.

"These studies establish proof-of-concept for in vivo cellular reprogramming as a new approach for heart repair," said Dr. Olson, professor and chair of molecular biology at UT Southwestern, and a co-founder of LoneStar Heart. "However, much work remains to be done to determine if this strategy might eventually be effective in humans. We are working hard toward that goal."

The new reprogramming strategy may provide a novel means of improving cardiac function following injury, bypassing many of the obstacles associated with cellular transplantation. Prior work by Dr. Olson's group and others has shown that GHMT proteins fulfill similar roles in cardiac gene regulation in a wide range of organisms, including humans, highlighting the potential of these proteins to augment function of the injured human heart. While cellular replacement strategies via the introduction of stem cells or other cell types into injured hearts have shown promise, there have been numerous technical and biological hurdles associated with such approaches.

About LoneStar Heart, Inc.LoneStar Heart, Inc. is developing cardiac restorative therapies for patients with heart failure that stimulate the heart's ability to repair itself. Based on its integrated cardiomechanical and biomolecular technologies, the privately held company is advancing a broad portfolio of products to restore the failing heart's structure and function in collaboration with the Texas Heart Institute, UT Southwestern, and a global network of leading clinicians. These products include Algisyl-LVR,cardiac stem-cell modulators, and cellular and genetic therapies delivered as stand-alone treatments, or in combination with the company's biopolymer matrix system.

LoneStar Heart's lead product, Algisyl-LVR, is a single-use, self-gelling biopolymer implanted into the heart's left ventricle during surgery. Providing internal tissue support, Algisyl-LVR is aimed at preventing the progression of heart failure and restoring the heart's normal structure and function with a significant improvement in the patient's quality of life. Classified as a medical device, the product is undergoing a randomized controlled clinical study (AUGMENT-HF) in Europe to evaluate its safety and efficacy in patients with advanced heart failure.

About UT Southwestern Medical CenterUT Southwestern Medical Center, one of the premier medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. Its faculty has many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,600, the faculty is responsible for groundbreaking medical advances and is committed to quickly translating science-driven research to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to more than 100,000 hospitalized patients, and oversee nearly 2 million outpatient visits a year.

Physicians care for patients in the Dallas-based UT Southwestern Medical Center; in Parkland Health & Hospital System, which is staffed primarily by UT Southwestern physicians; and in its affiliated hospitals, Children's Medical Center Dallas, Texas Scottish Rite Hospital for Children and the VA North Texas Health Care System. UT Southwestern programs are offered in Waco, Wichita Falls, Plano/Frisco and Fort Worth. Three degree-granting institutions UT Southwestern Medical School, UT Southwestern Graduate School of Biomedical Sciences and UT Southwestern School of Health Professions train nearly 4,600 students, residents and fellows each year. UT Southwestern researchers undertake more than 3,500 research projects annually, totaling more than $417 million.

Dr. Olson holds the Pogue Distinguished Chair in Research on Cardiac Birth Defects, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Professorship in Stem Cell Research at UT Southwestern.

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Heart Damage Repaired By Reprogramming Resident Fibroblasts into Functioning Heart Cells

ScienceDaily (May 28, 2012) Cardiomyocytes, the workhorse cells that make up the beating heart, can now be made cheaply and abundantly in the laboratory.

Writing this week (May 28, 2012) in the Proceedings of the National Academy of Sciences, a team of Wisconsin scientists describes a way to transform human stem cells -- both embryonic and induced pluripotent stem cells -- into the critical heart muscle cells by simple manipulation of one key developmental pathway. The technique promises a uniform, inexpensive and far more efficient alternative to the complex bath of serum or growth factors now used to nudge blank slate stem cells to become specialized heart cells.

"Our protocol is more efficient and robust," explains Sean Palecek, the senior author of the new report and a University of Wisconsin-Madison professor of chemical and biological engineering. "We have been able to reliably generate greater than 80 percent cardiomyocytes in the final population while other methods produce about 30 percent cardiomyocytes with high batch-to-batch variability."

The ability to make the key heart cells in abundance and in a precisely defined way is important because it shows the potential to make the production of large, uniform batches of cardiomyocytes routine, according to Palecek. The cells are in great demand for research, and increasingly for the high throughput screens used by the pharmaceutical industry to test drugs and potential drugs for toxic effects.

The capacity to make the heart cells using induced pluripotent stem cells, which can come from adult patients with diseased hearts, means scientists will be able to more readily model those diseases in the laboratory. Such cells contain the genetic profile of the patient, and so can be used to recreate the disease in the lab dish for study. Cardiomyocytes are difficult or impossible to obtain directly from the hearts of patients and, when obtained, survive only briefly in the lab.

Scientists also have high hopes that one day healthy lab-grown heart cells can be used to replace the cardiomyocytes that die as a result of heart disease, the leading cause of death in the United States.

"Many forms of heart disease are due to the loss or death of functioning cardiomyocytes, so strategies to replace heart cells in the diseased heart continue to be of interest," notes Timothy Kamp, another senior author of the new PNAS report and a professor of cardiology in the UW School of Medicine and Public Health. "For example, in a large heart attack up to 1 billion cardiomyocytes die. The heart has a limited ability to repair itself, so being able to supply large numbers of potentially patient-matched cardiomyocytes could help."

"These cells will have many applications," says Xiaojun Lian, a UW-Madison graduate student and the lead author of the new study. The beating cells made using the technique he devised have, so far, been maintained in culture in the lab for six months and remain as viable and stable as the day they were created.

Lian and his colleagues found that manipulating a major signaling pathway known as Wnt -- turning it on and off at prescribed points in time using just two off-the-shelf small molecule chemicals -- is enough to efficiently direct stem cell differentiation to cardiomyocytes.

"The fact that turning on and then off one master signaling pathway in the cells can orchestrate the complex developmental dance completely is a remarkable finding as there are many other signaling pathways and molecules involved," says Kamp.

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New stem cell technique promises abundance of key heart cells

Five UC San Diego scientists have received almost $12 million combined from the California Institute for Regenerative Medicine to pay for stem cell-based research, the university announced today.

A team led by Lawrence Goldstein, of the Department of Cellular and Molecular Medicine and director of the UC San Diego Stem Cell Program, was given $1.8 million to continue looking for new methods to find and test possible medications for Alzheimer's disease, according to UCSD. They use reprogrammed stem cells in their work.

Dr. Mark Tuszynski, professor of neurosciences and director of the Center for Neural Repair, received $4.6 million to develop more potent stem cell-based treatments for spinal cord injuries.

Gene Yeo, assistant professor in the Department of Cellular and Molecular Medicine, was awarded $1.6 million to continue research into treatments for amyotrophic lateral sclerosis. His research hopes to take advantage of recent discoveries about ALS, or Lou Gehrig's disease, which center on mutations in RNA-binding proteins that cause dysfunction and death in neurons.

Dr. Eric David Adler, an associate clinical professor of medicine and cardiologist, was granted $1.7 million to screen potential drugs for Danon disease, a type of inherited heart failure that frequently kills patients by their 20s.

Yang Xu, a professor in the Division of Biological Sciences, was given $1.8 million to research the use of human embryonic stem cells to produce a renewable source of heart muscle cells that replace cells damaged or destroyed by disease, while overcoming biological resistance to new cells.

"With these new awards, the (institute) now has 52 projects in 33 diseases at varying stages of working toward clinical trials,'' said Jonathan Thomas, chairman of the CIRM governing board. "Californians should take pride in being at the center of this worldwide research leading toward new cures.''

CIRM was established in November 2004 with voter passage of the California Stem Cell Research and Cures Act. UC San Diego has received $112 million since CIRM began providing grants six years ago.

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UC San Diego Scientists Net $12 Million For Stem Cell Research

HAMILTON An antipsychotic drug found by McMaster University researchers to kill cancer stem cells was pulled from the shelves by Health Canada years ago because of safety concerns.

Thioridazine could dramatically change cancer treatment. The researchers recently discovered it reduced leukemia stem cells by 50 per cent in 24 hours in mice injected with primary human samples.

We have certainly not seen any drug weve ever tested have that kind of potency, said Dr. Mick Bhatia, scientific director of McMasters Stem Cell and Cancer Research Institute and principal investigator of the study published Thursday in the science journal Cell.

Thioridazine is also remarkable because its a smart drug that kills only cancer stem cells and appears to have no effect on normal cells. As a result, it avoids the toxic side-effects of conventional cancer treatments.

Were excited we have something interesting, but were always nervous because we want to make sure it helps people, said Bhatia. The impact of this will be determined if we can put some patients in remission and certainly thats my romantic goal.

But there are questions about the safety of the drug. Health Canada halted sales of thioridazine in September 2005.

It was pulled because it can cause a serious type of irregular heartbeat that may cause sudden death. Three deaths in Canada between 2000 and 2005 were reported by Health Canada to be possibly related to thioridazine.

Concerns started to be raised in 2000 about the drug used to treat schizophrenia since 1959.

Its no longer approved in Canada and is only used as a last-ditch hope in the United States for schizophrenia patients who have already tried at least two other antipsychotic medications.

But Bhatia believes it will be safer for cancer patients because they only take it for eight to 21 days instead of a number of years, and they need half the dose.

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Schizophrenia drug may help prevent some cancers from recurring: study

An antipsychotic drug found by McMaster University researchers to kill cancer stem cells was pulled from the shelves by Health Canada years ago because of safety concerns.

Thioridazine could dramatically change cancer treatment. The researchers recently discovered it reduced leukemia stem cells by 50 per cent in 24 hours in mice injected with primary human samples.

We have certainly not seen any drug weve ever tested have that kind of potency, said Dr. Mick Bhatia, scientific director of McMasters Stem Cell and Cancer Research Institute and principal investigator of the study published Thursday in the science journal CELL.

Thioridazine is also remarkable because its a smart drug that kills only cancer stem cells and appears to have no effect on normal cells. As a result, it avoids the toxic side-effects of conventional cancer treatments.

Were excited we have something interesting, but were always nervous because we want to make sure it helps people, said Bhatia. The impact of this will be determined if we can put some patients in remission and certainly thats my romantic goal.

But there are questions about the safety of the drug. Health Canada halted sales of Thioridazine in September 2005.

It was pulled because it can cause a serious type of irregular heartbeat that may cause sudden death. Three deaths in Canada between 2000 and 2005 were reported by Health Canada to be possibly related to thioridazine.

Concerns started to be raised in 2000 about the drug used to treat schizophrenia since 1959.

Its no longer approved in Canada and is only used as a last-ditch hope in the United States for schizophrenia patients who have already tried at least two other antipsychotic medications.

But Bhatia believes it will be safer for cancer patients because theyre only on it for eight to 21 days instead of a number of years, and they take half the dose.

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Drug that kills cancer stem cells has safety concerns

Editor's Choice Main Category: Bones / Orthopedics Also Included In: Stem Cell Research Article Date: 22 May 2012 - 12:00 PDT

Current ratings for: 'Prochymal - First Stem Cell Drug Approved'

4.5 (2 votes)

Prochymal (remestemcel-L) is also the first drug to be approved for the treatment of acute graft-vs-host disease (GvHD) in children, a devastating complication of bone marrow transplantation that kills almost 80% of all affected children, many of which just weeks after they have been diagnosed.

GvHD is the leading cause of transplant-related mortality, caused by an immunologic attack. Severe GvHD can cause blistering of the skin, intestinal hemorrhage and liver failure and is extremely painful with a death rate of up to 80%. At present, the first-line standard therapies for GvHD are steroids. Given that the success rate of steroids is only 30 to 50%, the only other therapy if steroids fail is limited to immunosuppressive agents that are used off-label with little benefit and significant toxicities. Until the approval of Prochymal, there has not been any other therapy for GvHD.

Osiris Therapeutics Inc. was awarded authorization for Prochymal under Health Canada's Notice of Compliance with conditions (NOC/c). A NOC/c is an authorization to market a drug with the condition that the manufacturer undertakes additional studies to verify the clinical benefit. This pathway provides access to treatments for unmet medical conditions and has demonstrated its benefits outweigh its risks in clinical trials.

Andrew Daly, M.D., Clinical Associate Professor from the Department of Medicine and Oncology at the University of Calgary, Canada and leading researcher of Prochymal's phase 3 clinical program declared:

C. Randal Mills, Ph.D., President and Chief Executive Officer of Osiris announced:

Prochymal is an intravenous formulation of mesenchymal stem cells (MSCs), which are derived from the bone marrow of healthy adult donors aged between 18 and 30 years. The MSCs are selected from the bone marrow and grown in culture, producing up to 10,000 doses of Prochymal from a single donor. The drug is a true off-the-shelf stem cell product, which is stored frozen until it is needed. Prochymal is infused through a simple intravenous line without the need to type or immunosuppress the recipient. The drug is currently undergoing Phase 3 trials for refractory Crohn's disease, as well as undergoing clinical trials for the treatment of heart attacks and type-1 diabetes.

Health Canada granted the Prochymal's authorization for the management of acute GvHD in children who are unresponsive to steroids, based on the drug's results of clinical trials. Prochymal was recommended by an independent expert advisory panel, which was commissioned to assess the drugs safety and efficacy.

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Prochymal - First Stem Cell Drug Approved

By Kristen Hallam - 2012-05-22T23:05:00Z

Israeli scientists for the first time succeeded in transforming the skin cells of heart-failure patients into healthy heart-muscle cells, suggesting that it may be possible to repair the organ with a persons own tissue.

The cells from two men with the disease, once genetically reprogrammed, were able to blend in with healthy heart tissue in rats, scientists from the Technion-Israel Institute of Technology and Rambam Medical Center in Haifa, wrote today in the European Heart Journal, a publication of the European Society of Cardiology. Testing the cells in human hearts may be as long as a decade away, as scientists hone the technique in animal studies, they said.

The finding points to a novel potential source of stem cells, the building blocks of life which can grow into any type of tissue in the body. Using skin cells from the patient would avoid the difficulty of obtaining stem cells from embryos and may limit the risk that the patients immune system would reject the transplant, which can occur with cells taken from healthy people and given to the sick, the researchers said.

We have shown that its possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young, the equivalent to the stage of his heart cells when he was just born, said Lior Gepstein, a professor of medicine and physiology who led the research, in a statement.

Heart failure is a weakening of the heart muscle that can cause fatigue and ultimately death. About 5.8 million people in the U.S. have the condition, according to the National Institutes of Health. More people are surviving heart attacks and, as a result, the number of people living with a damaged heart is increasing, said Nicholas Mills, an intermediate clinical research fellow at the British Heart Foundation and a cardiologist at the University of Edinburgh.

Unfortunately, the body has only very limited capacity to repair the heart following a heart attack, Mills said in a statement. There is therefore an urgent need to develop effective and safe treatments to regenerate the heart.

The study published today was funded by the Israel Science Foundation, the European Research Council, the Nancy and Stephen Grand philanthropic fund, and the J&J-Technion research grant.

More research is needed to determine whether the cells can be produced in enough quantity for effective treatment and to develop transplantation strategies that reduce the risk of the body rejecting the cells, the scientists said. Refining the procedure will probably require funding from the pharmaceutical and biotechnology industries, said Gepstein, whose team is conducting additional experiments in animals.

I assume it will take at least five to 10 years to clinical trials if one can overcome these problems, Gepstein said.

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Heart-Failure Patients’ Cells May Be Used for Repair

WOONSOCKET, R.I., May 16, 2012 /PRNewswire/ --MultiCell Technologies, Inc. (MCET.OB) is pleased to announce representatives from the Company will present preclinical research findings for MCT-465 and MCT-485 at CIMT 2012 (http://meeting.cimt.eu), Europe's largest meeting dedicated to cancer immunotherapy research and development. CIMT 2012 will be held in May 23-25 in Mainz, Germany. The title of the poster presentation is: "Sharply discordant biological properties of synthetic noncoding dsRNA of different size: Translational opportunities in cancer."The poster presentation in the Enhancing Immunity session of the conference (poster number 078) will be made by Dr. Simona Bot, a consultant to the Company. The Company will present its findings during Poster Session I held on May 23rd, from 3:00-4:30 PM, and Poster Session II held on May 24th from 4:00-5:30 PM.

About MCT-465 and MCT-485

MCT-465 and MCT-485 are the first of a family of prospective cancer therapeutics based on the use of our patented TLR3 signaling technology. MCT-465 and MCT 485 are in preclinical development, and are being investigated as prospective treatments for primary liver cancer and triple negative breast cancer.

The immune system is composed of two synergistic elements: the innate immune system and the adaptive immune system. Stimulation of the innate immune system through key receptors, plays a critical role in triggering the adaptive immune response stimulating T and B cells to produce antibodies. In cancer, this integrated defense system does not work well, resulting in suboptimal activation of innate immunity and thus, late or inefficient adaptive immunity. The innate immune system is composed of a family of ten receptor molecules, the Toll-like Receptors (TLR1-TLR10), which act as sentries to identify invaders and signal the alarm to mobilize the body's array of immune defenses.

Within the tumor lesion, there may be infiltrating monocytes, dendritic cells and leukocytes in general, that have the capability to mobilize an adaptive or innate immune response but they are either silent or immune suppressive in the absence of select immune interventions. Such infiltrating non-cancerous immune cells may express TLR3, other TLRs, RIG-I and/or MDA-5. In addition, within tumor lesions, there may be cancerous cells or stromal cells or cancer stem cells which express TLR3, other TLRs, RIG-I and MDA-5 (representing RNA-sensing molecules).

Cancer stem cells are thought to play a role in a tumor's resistance to therapy. While significant progress has been made in developing cancer therapies that result in cytoreduction and thus tumor regression, the control of cancer over a longer interval and especially of metastatic disease, remains a key goal. Cancer stem cells are believed to be responsible for cancer relapse by being less sensitive to conventional therapies.

MultiCell owns exclusive rights to two issued U.S. patents (6,872,389 and 6,129,911), one U.S. patent application (U.S. 2006/0019387A1), and several corresponding issued and pending foreign patents and patent applications related to the isolation and differentiation of liver stem cells. The role of liver stem cells in the carcinogenic process has recently led to a new hypothesis that hepatocellular carcinoma arises by maturation arrest of liver stem cells.

Double stranded RNA provides a therapeutic avenue for cancer treatment through (a) activating intra-tumoral leukocytes, abrogating their immune suppressive activity and/or (b) interacting with cancerous cells and directly inducing apoptosis, or indirectly through mobilization of immune effector mechanisms.

MCT-465 is a high molecular weight synthetic dsRNA (polyA:polyU, of 70bps) with immune enhancing properties. The mechanism of action of MCT-465 is pleiotropic and mediated by RNA sensors such as TLR3, 7/8, MDA-5 and RIG-I - expressed by antigen presenting cells and select cases, by tumor cells:

Prior studies with similar compounds support a strong immune enhancing effect of MCT-465, consisting in generation of Tc immunity against tumors, when administered as a companion to a vaccine. This raises the possibility that MCT-465 is an effective adjunctive therapy to any small molecule targeted therapy (such as tyrosine kinase inhibitors - TKIs) that results in release of endogenous tumor antigen while interfering minimally with the immune competence.

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MultiCell Technologies Announces Positive Preclinical Results for MCT-465 and MCT-485 in Primary Liver Cancer In Vitro ...

ScienceDaily (May 2, 2012) Research led by vascular surgeons at Dartmouth-Hitchcock may offer new hope to sufferers of peripheral artery disease, the cause of nearly 60,000 lower-limb amputations annually, through the use of a patient's own stem cells.

Richard J. Powell MD, chief of vascular surgery at Dartmouth-Hitchcock, is the principal investigator on a national study -- involving 550 patients at 80 sites around the country -- of so-called "no option" patients, for whom the disease is so advanced that amputation is the only available treatment.

Powell's study is now in a three-year, third-stage clinical trial, after second-stage trials showed remarkable success at treating patients with CLI. The final results of the second-stage clinical trial have been published in the April, 2012, issue of Molecular Therapy.

Peripheral artery disease (PAD) afflicts more than 9 million patients in the United States. The condition results from blockages in blood vessels caused by atherosclerosis -- hardening of the arteries -- which can be a consequence of diabetes, high cholesterol, smoking, genetic predisposition, and other circumstances. In many cases, endovascular therapies such as insertion of stents or bypass surgery -- similar to surgical processes used to treat blockages in the arteries of the heart -- are used to reintroduce blood flow to the legs. But in about 150,000 patients with the most-severe forms of PAD, called critical limb ischemia or CLI, the disease is so extensive that endovascular therapy isn't an option. That's where Powell's stem cell study comes in.

"All of us have stem cells in our bone marrow, and these stem cells can be utilized to repair other parts of our bodies," says Powell. "By taking the patient's own stem cells and injecting them into the ischemic leg, our hope is that we will then improve the blood flow in that part of the leg."

In the study, bone marrow is removed from the patient's hip, and then sent to a lab where stem cells are separated from the marrow and incubated over a two-week period, allowing more stem cells to grow. The stem cells are then re-injected intramuscularly into about 20 different spots on the patient's leg.

"We found that patients who received the stem cell therapy had a significantly lower incidence of amputation at six months than patients who received a placebo," said Powell.

After six months of the second-stage trials, approximately half of the patients who received a placebo died, required an amputation or saw their leg wounds worsen. Of those receiving the stem cell therapy, only a quarter died, required amputation, or saw their wounds worsen. Many showed significant improvement in blood flow in the ischemic limb.

"What was truly remarkable was that it was a relatively small number of patients, but that we saw clinically significant improvement in the stem cell-treated patients," he says. "It's compelling enough that there's no question that the pivotal trial needs to be done as quickly as possible."

The phase three trial has just begun, in which half of the patients will receive stem cell therapy and half will receive the placebo, measuring incidents of amputation or death one year after the treatment "We really want to see a therapy that's effective out to a year," says Powell. "Nonetheless, the results so far are really promising."

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New hope for PAD sufferers

Human embryonic stem cells swiftly kill themselves in response to DNA damage.

Human embryonic stem cells give a whole new meaning to the phrase taking one for the team. Unlike any other known human cell type, hESCs are primed to immediately throw themselves on the sword if they experience any DNA damage, according to research published online today (May 3) in Molecular Cell.

Human embryonic stem cells (hESCs) form the early embryo and eventually give rise to every cell type in the body. Because of this, a rapid self-destruct mechanism activated by DNA damage may prevent potentially dangerous mutations from spreading through the developing organism, the authors concluded.

The data is convincing, wrote Christopher Navara, who studies stem cells at the University of Texas at San Antonio and was not involved in the research, in an email to The Scientist. hES cells have adopted a number of unique cell cycle and cell death regulatory mechanisms to balance their rapid proliferation with maintaining a stable, healthy genome, he wrote.

Four years ago, Mohanish Deshmukh and colleagues at the University of North Carolina at Chapel Hill found that neuronswhich, unlike stem cells, do not dividerestrict apoptosis, or cell death, allowing them to survive through periods of stress or cell damage that might otherwise stimulate apoptosis. To explore apoptosis at the other end of the development spectrum, the researchers next analyzed human ESCs, which constantly divide.

They had two hypotheses: the hESCs would be highly resistant to apoptosis since there are only about 50 of them in the early embryo and thus each is valuable; or they would be highly sensitive to apoptosis since DNA damage in even a single cell would quickly spread through an embryo. We figured it could go either way, said Deshmukh. We were very curious.

First, the team doused hESCs in a chemotherapy drug that causes DNA damage. Almost 100 percent of the hESCs died in just 5 hours, compared to 24 hours for fibroblasts. The finding is consistent with what we and others have observed regarding sensitivity to DNA damage in hES cells, said Navara.

When Deshmukhs team stressed the ESCs in other ways, such as damaging the cytoskeleton, the cells did not die as quickly, demonstrating their acute sensitivity to DNA damage. DNA damage is the one insult these embryonic stem calls cant tolerate, said Deshmukh. Its catastrophic for them. Any mutations they occur will be propagated rapidly through the system.

Apoptosis is traditionally a lengthy process that involves the activation of a protein called Bax, which travels to the mitochondria and initiates the release of caspases, or executioner proteins that cause cell death. To investigate how hESCs initiate the process so rapidly, the researchers tagged Bax with an antibody that lights up when the protein is active. They were surprised to find that Bax is already active in healthy hESCs, unlike every other cell type in which Bax is activated only when a cell is damaged or dying. I was stunned, said Deshmukh. I thought something was wrong. We spent a lot of time convincing ourselves that these cells were healthy and not actively dying.

The team also saw that active Bax was not located in the mitochondria but in the Golgi, a packaging organelle. It is possible that cells sequester active Bax there, like a gun locked in a case, to prevent it from accidentally triggering cell death. The cells activated it and tethered it to a place where it is not causing immediate damage, said Deshmukh. That way, Bax is ready to go at a moments notice.

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Stem Cell Suicide Switch

NES ZIONA, Israel--(BUSINESS WIRE)--

Kadimastem, an Israeli Biotechnology company that develops human pluripotent stem cell-related products, today announced the signing of a five year framework agreement with Merck Serono, a division of Merck KGaA, Darmstadt, Germany. The agreement concerns the use of Kadimastem's drug-screening platform to discover new oral drugs for the treatment of the neurological disease Multiple Sclerosis (MS).

The system developed by Kadimastem allows using human functional tissues produced industrially from pluripotent stem cells as a means to search for potential new drugs, a direct approach that has advantages over the use of animals. In Multiple Sclerosis, the insulating myelin sheaths which cover many nerves in the brain and spinal cord are destroyed due to loss of the myelin-forming cells resulting in the impairment of nerve function and severe neurological disabilities. It is estimated that 2.5 million patients suffer from this disease around the globe. While the existing treatments act by slowing down the loss of myelin-forming cells, there is great interest in finding new medications that could repair the myelin by stimulating the regeneration of myelin-forming cells. The drug-screening project, to be carried out through the Kadimastem-Merck Serono agreement, aims precisely at the discovery of potential oral drugs that act by stimulating myelin repair.

We are pleased to announce this agreement with Merck-Serono, a company with robust experience in drug discovery, development and marketing in the Multiple Sclerosis area, said Mr. Yossi Ben-Yossef, CEO of Kadimastem. The undisclosed compensation for this agreement will provide financial support for Kadimastem's own in-house drug discovery initiatives, in the field of neurodegenerative diseases as well as in the field of Diabetes. Kadimastem also produces pancreatic islet cells from pluripotent stem cells, for screening of drugs enhancing insulin secretion and eventually for cellular therapy of Diabetes.

Prof. Michel Revel, Chief Scientist of Kadimastem, further commented: We are very proud that after a thorough evaluation, Merck Serono decided to sign an agreement with us. We see it as a proof of our excellence in developing human myelin-forming cells and our capabilities in drug screening. We believe that this agreement is a first step towards further collaboration with Merck Serono and other Pharmaceutical companies, in which our capabilities in drug screening on human functional cell systems will synergize with their capabilities in medicinal chemistry and clinical development, to make drugs available more rapidly and more efficiently.

Prof. Revel from the Weizmann Institute of Science was the Chief Scientist of InterPharm, an Israeli biotech company part of the Merck Serono group that developed Prof. Revel's groundbreaking research which lead to Rebif (mammalian cell-produced recombinant Interferon beta-1a), today a leading drug for the treatment of Multiple Sclerosis with annual sales by Merck Serono of over US$ 2.3 billion.

Mr. Amir Naiberg, CEO of Yeda, the commercial arm of the Weizmann Institiute of Science, said: We are excited that Kadimastem, that was established around one of our technologies, is collaborating with Merck Serono. Merck Serono has a long and successful tradition of developing products that emerged from the Weizmann Institute labs,and we hope that Kadimastem will be another link in this chain.

About Kadimastem

Kadimastem (www.kadimastem.com) is a biotechnology company focused on the industrial development and commercialization of human pluripotent stem cell-based products. At Kadimastem, the pluripotent stem cell technology is used to produce specialized human cells and tissues for two major types of medical applications: 1) Drug-screening platforms using human functional cells and tissues as in vitro assays for discovering novel therapeutic drugs for neurological diseases and diabetes, and 2) Cell therapy for regenerative medicine, to repair tissues and organs affected by diseases, such as implanting insulin-secreting pancreatic islet cells as a treatment for insulin-dependent diabetes. Kadimastem is developing these technologies in its state of the art 1,000 m2 facilities in the Weizmann Science Park (Ness Ziona, Israel), for industrial research and production, with a staff of PhD-level and MSc-level scientists. Kadimastem uses pluripotent human stem cells made available through licensing agreements with the Embryonic Stem Cell Center of the Hadassah Medical center in Jerusalem (Prof. Benjamin Reubinoff) and the Shaarei Zedek Medical Center, Jerusalem, Israel.

About Merck Serono

Link:
Pharmaceutical Company Merck Serono Signs an Agreement to Use Kadimastem's Platform for Drug Screening

Eliminating smoking at home reduces the risk of sudden infant death syndrome (SIDS) by 80 percent, an Australian study has found.

Research from the University of Sydney has proven a link between noxious fumes and SIDS. It found nicotine, the main neurotoxin found in cigarette smoke, increased the risk of SIDS by damaging brain stem cells receptive to the drug.

The results, published in the journal of Toxicology and Applied Pharmacology, followed up on the research team's previous 2007 study of babies who died of SIDS that proved any smoke exposure contributed to brain cell death.

Of the 67 babies who died of SIDS in the research group, 81 percent were exposed to cigarette smoke.

International studies have shown the babies of mothers who smoke during pregnancy have a five-fold increase in the risk of SIDS, while babies born into a home where there is a smoker have a three-fold risk.

"We found any smoke exposure in the home resulted in a greater number of cells dying in the brain stem which controls heart rate, respiration and sleep and arousal," researcher Dr. Rita Machaalani said.

The incidence of SIDS has decreased by 85 percent in the past 25 years due to safe sleep education programs that recommend babies be placed on their backs to sleep.

Almost one in five women still smoke in pregnancy, including 42 percent of teenagers and 52 percent of indigenous women.

"The most outstanding risk factor is tobacco smoke and it's one of the hardest ones to shake," Ros Richardson, from SIDS and Kids NSW, said.

"Smoking in pregnancy is also associated with a higher risk of stillbirth and pre-term birth and neonatal loss."

See the original post here:
Study finds smoking leads to increase in sudden infant death syndrome

April 20, 2012 18:19 PM

IBN Discovers Human Neural Stem Cells, Promising Discovery For Breast Cancer Therapy

By Tengku Noor Shamsiah Tengku Abdullah

SINGAPORE, April 20 (Bernama) -- Could engineered human stem cells hold the key to cancer survival?

Scientists at the Institute of Bioengineering and Nanotechnology (IBN), the world's first bioengineering and nanotechnology research institute, have discovered that neural stem cells possess the innate ability to target tumor cells outside the central nervous system.

This finding, which was demonstrated successfully on breast cancer cells, was recently published in leading peer reviewed journal, Stem Cells.

Despite decades of cancer research, cancer remains a leading cause of death worldwide, accounting for 7.6 million deaths in 2008, and breast cancer is one of the most common causes of cancer deaths each year.

In Singapore, more than 1,400 women are diagnosed with breast cancer and more than 300 die as a result of breast cancer annually.

A team of researchers led by IBN group leader Dr Shu Wang, has made a landmark discovery that neural stem cells (NSCs) derived from human induced pluripotent stem (iPS) cells could be used to treat breast cancer.

The effectiveness of using NSCs, which originate from the central nervous system, to treat brain tumors has been investigated in previous studies.

View original post here:
IBN Discovers Human Neural Stem Cells, Promising Discovery For Breast Cancer Therapy

Despite decades of cancer research, cancer remains a leading cause of death worldwide, accounting for 7.6 million deaths in 2008, and breast cancer is one of the most common causes of cancer deaths each year . In Singapore, more than 1,400 women are diagnosed with breast cancer and more than 300 die as a result of breast cancer each year . The high fatality rate of cancer is partially attributed to the invasive ability of malignant tumors to spread throughout the human body, and the ineffectiveness of conventional therapies to eradicate the cancer cells.

A team of researchers led by IBN Group Leader, Dr Shu Wang, has made a landmark discovery that neural stem cells (NSCs) derived from human induced pluripotent stem (iPS) cells could be used to treat breast cancer. The effectiveness of using NSCs, which originate from the central nervous system, to treat brain tumors has been investigated in previous studies. This is the first study that demonstrates that iPS cell-derived NSCs could also target tumors outside the central nervous system, to treat both primary and secondary tumors.

To test the efficiency of NSCs in targeting and treating breast cancer, the researchers injected NSCs loaded with a suicide gene (herpes simplex virus thymidine) into mice bearing breast tumors. They did this using baculoviral vectors or gene carriers engineered from an insect virus (baculovirus), which does not replicate in human cells, making the carriers less harmful for clinical use. A prodrug (ganciclovir), which would activate the suicide gene to kill the cancerous cells upon contact, was subsequently injected into the mice. A dual-colored whole body imaging technology was then used to track the distribution and migration of the iPS-NSCs.

The imaging results revealed that the iPS-NSCs homed in on the breast tumors in the mice, and also accumulated in various organs infiltrated by the cancer cells such as the lung, stomach and bone. The survival of the tumor-bearing mice was prolonged from 34 days to 39 days. This data supports and explains how engineered iPS-NSCs are able to effectively seek out and inhibit tumor growth and proliferation.

Dr Shu Wang shared, "We have demonstrated that tumor-targeting neural stem cells may be derived from human iPS cells, and that these cells may be used in combination with a therapeutic gene to cripple tumor growth. This is a significant finding for stem cell-based cancer therapy, and we will continue to improve and optimize our neural stem cell system by preventing any unwanted activation of the therapeutic gene in non-tumor regions and minimizing possible side effects."

"IBN's expertise in generating human stem cells from iPS cells and our novel use of insect virus carriers for gene delivery have paved the way for the development of innovative stem cell-based therapies. With their two-pronged attack on tumors using genetically engineered neural stem cells, our researchers have discovered a promising alternative to conventional cancer treatment," added Professor Jackie. Y. Ying, IBN Executive Director.

Compared to collecting and expanding primary cells from individual patients, IBN's approach of using iPS cells to derive NSCs is less laborious and suitable for large-scale manufacture of uniform batches of cellular products for repeated patient treatments. Importantly, this approach will help eliminate variability in the quality of the cellular products, thus facilitating reliable comparative analysis of clinical outcomes.

Additionally, these iPS cell-derived NSCs are derived from adult cells, which bypass the sensitive ethical issue surrounding the use of human embryos, and since iPS cells are developed from a patient's own cells, the likelihood of immune rejection would be reduced.

References: 1. J. Yang, D. H. Lam, S. S. Goh, E. X. L. Lee, Y. Zhao, F. Chang Tay, C. Chen, S. Du, G. Balasundaram, M. Shahbazi, C. K. Tham, W. H. Ng, H. C. Toh and S. Wang, "Tumor Tropism of Intravenously Injected Human Induced Pluripotent Stem Cell-derived Neural Stem Cells and their Gene Therapy Application in a Metastatic Breast Cancer Model," Stem Cells, (2012) DOI: 10.1002/stem.1051.

2. E. X. Lee, D. H. Lam, C. Wu, J. Yang, C. K. Tham and S. Wang, "Glioma Gene Therapy Using Induced Pluripotent Stem Cell-Derived Neural Stem Cells," Molecular Pharmaceutics, 8 (2011) 1515-1524.

Read more from the original source:
IBN Discovers Human Neural Stem Cells with Tumor Targeting Ability - A Promising Discovery for Breast Cancer Therapy

ScienceDaily (Apr. 20, 2012) Could engineered human stem cells hold the key to cancer survival? Scientists at the Institute of Bioengineering and Nanotechnology (IBN), the world's first bioengineering and nanotechnology research institute, have discovered that neural stem cells possess the innate ability to target tumor cells outside the central nervous system.

This finding, which was demonstrated successfully on breast cancer cells, was recently published in peer reviewed journal, Stem Cells.

Despite decades of cancer research, cancer remains a leading cause of death worldwide, accounting for 7.6 million deaths in 2008, and breast cancer is one of the most common causes of cancer deaths each year[1]. In Singapore, more than 1,400 women are diagnosed with breast cancer and more than 300 die as a result of breast cancer each year[2]. The high fatality rate of cancer is partially attributed to the invasive ability of malignant tumors to spread throughout the human body, and the ineffectiveness of conventional therapies to eradicate the cancer cells.

A team of researchers led by IBN Group Leader, Dr Shu Wang, has made a landmark discovery that neural stem cells (NSCs) derived from human induced pluripotent stem (iPS) cells could be used to treat breast cancer. The effectiveness of using NSCs, which originate from the central nervous system, to treat brain tumors has been investigated in previous studies. This is the first study that demonstrates that iPS cell-derived NSCs could also target tumors outside the central nervous system, to treat both primary and secondary tumors.

To test the efficiency of NSCs in targeting and treating breast cancer, the researchers injected NSCs loaded with a suicide gene (herpes simplex virus thymidine) into mice bearing breast tumors. They did this using baculoviral vectors or gene carriers engineered from an insect virus (baculovirus), which does not replicate in human cells, making the carriers less harmful for clinical use. A prodrug (ganciclovir), which would activate the suicide gene to kill the cancerous cells upon contact, was subsequently injected into the mice. A dual-colored whole body imaging technology was then used to track the distribution and migration of the iPS-NSCs.

The imaging results revealed that the iPS-NSCs homed in on the breast tumors in the mice, and also accumulated in various organs infiltrated by the cancer cells such as the lung, stomach and bone. The survival of the tumor-bearing mice was prolonged from 34 days to 39 days. This data supports and explains how engineered iPS-NSCs are able to effectively seek out and inhibit tumor growth and proliferation.

Dr Shu Wang shared, "We have demonstrated that tumor-targeting neural stem cells may be derived from human iPS cells, and that these cells may be used in combination with a therapeutic gene to cripple tumor growth. This is a significant finding for stem cell-based cancer therapy, and we will continue to improve and optimize our neural stem cell system by preventing any unwanted activation of the therapeutic gene in non-tumor regions and minimizing possible side effects."

"IBN's expertise in generating human stem cells from iPS cells and our novel use of insect virus carriers for gene delivery have paved the way for the development of innovative stem cell-based therapies. With their two-pronged attack on tumors using genetically engineered neural stem cells, our researchers have discovered a promising alternative to conventional cancer treatment," added Professor Jackie. Y. Ying, IBN Executive Director.

Compared to collecting and expanding primary cells from individual patients, IBN's approach of using iPS cells to derive NSCs is less laborious and suitable for large-scale manufacture of uniform batches of cellular products for repeated patient treatments. Importantly, this approach will help eliminate variability in the quality of the cellular products, thus facilitating reliable comparative analysis of clinical outcomes.

Additionally, these iPS cell-derived NSCs are derived from adult cells, which bypass the sensitive ethical issue surrounding the use of human embryos, and since iPS cells are developed from a patient's own cells, the likelihood of immune rejection would be reduced.

See the original post:
Human neural stem cells with tumor targeting ability discovered

The new suspension method allows stem cells to be collected in larger numbers instead of being scraped off of a surface

Researchers from the University of Toronto's Institute of Biomaterials and Biomedical Engineering (IBBME) have created a new method for growing stem cells in larger quantities.

David Fluri, a postdoctoral researcher at IBBME, and Peter Zandstra, a professor at IBBME, have developed a new suspension method for growing stem cells, which allows for the collection of greater numbers of stem cells and increases the chance of obtaining viable cells in a cost-effective way.

Traditionally, stem cells are grown on surfaces that need to be scraped and are then differentiated from other kinds of cells to avoid cell death. However, this method doesn't produce enough viable stem cells from each culture, and the high cost to use this method doesn't match the results.

But now, Fluri and Zandstra have combined the stem cell creation process with a bioreactor, which provides stable environments for such processes. The cells were also grown in suspension, making the process more stable and safer for more viable cells.

By doing this, mouse cells were reprogrammed into pluripotent stem cells, which can become any kind of cell. They were then changed into cardiac cells.

Fluri and Zandstra hope that this new technique can be used to eventually treat heart disease. It is designed to work with large scale processes and provide the quantity needed for successful stem cell research and drug development.

"This is an enabling technology," said Zandstra. "It takes something we showed we could do before at low efficiency but not at such numbers that could be used in manufacturing."

Source: Eurekalert

See the original post here:
Canadian Researchers Find Way to Grow Stem Cells in Larger Quantities

STROKE BACKGROUND: A stroke is an attack on the brain. It occurs when the blood supply to part of the brain is interrupted or severely reduced, depriving brain tissue of oxygen and food. Within minutes, brain cells begin to die.In the United States alone, stroke is the third leading cause of death, killing about 137,000 people each year. Approximately 795,000 people will suffer from some form of stroke this year. Strokes can happen to anyone at any time, regardless of race, sex or age and it is the leading cause of serious, long-term adult disability. (SOURCE: http://www.stroke.org, http://www.mayoclinic.com)

TYPES OF STROKES: There are two major types of strokes: ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when arteries are blocked by blood clots or by the gradual build-up of plaque and other fatty deposits. Hemorrhagic stroke occurs when a blood vessel in the brain breaks leaking blood into the brain. SOURCE: (www.stroke.org).

THINGS YOU MIGHT NOT KNOWN: Approximately 55,000 more women than menhave a stroke each year. Mens stroke incidence rates are greater than womens at younger ages, but not older ages; and African Americans are twice as likely of having a stroke compared to whites. About 87 % of all strokes are ischemic. Hemorrhagic strokes account for 13% of all strokes, yet are responsible for more than thirty percent of all stroke deaths. SOURCE: (www.stroke.org)

DETECTION: Use the F.A.S.T. to detect signs of a Stroke:

F = FACE Ask the person to smile. Does one side of the face droop? A = ARMS Ask the person to raise both arms. Does one arm drift downward? S = SPEECH Ask the person to repeat a simple sentence. Does the speech sound slurred or strange? T = TIME If you observe any of these signs (independently or together), call 9-1-1 immediately. SOURCE: (www.stroke.org)

PREVENTION: There are ways to prevent a stroke, such as: Not smoking or quitting smoking; controlling your cholesterol, blood pressure, and diabetes; exercising at least 30 minutes a day; maintaining a healthy weight; and limiting how much alcohol you drink. This means 1 drink a day for women and 2 a day for men. SOURCE: (www.ncbi.nlm.nih.gov/pubmedhealth)

LIFE AFTER A STROKE: Stroke rehabilitation is the process by which a stroke survivor works with a team of health care providers with the aim of regaining as much of the function lost after a stroke as possible. By joining a comprehensive rehabilitation program immediately after leaving the hospital, stroke survivors can maximize their chances of recovery, and in most cases they can regain a substantial portion of the functions they lost as a result of their stroke.

Some of the different types of medical professionals who participate in the care of stroke patients during the rehabilitation process include:

1. Physical Medicine and Rehabilitation Physicians (Physiatrists)

2 .Physical Therapists

More:
Stem cells for stroke?

Trial Provides Proof-of-Concept for Cell-Based Therapy in a Myelination Disorder

Company to Host Conference Call Today to Discuss Summary Results

NEWARK, Calif., April 2, 2012 (GLOBE NEWSWIRE) -- StemCells, Inc. (Nasdaq:STEM - News) today announced preliminary evidence of progressive and durable donor-cell derived myelination in all four patients who underwent transplantation with the Company's proprietary HuCNS-SC(R) cells (purified human neural stem cells) in its clinical trial for Pelizaeus-Merzbacher disease (PMD), a rare hypo-myelination disorder in children. In addition, clinical assessment revealed small but measureable gains in motor and/or cognitive function in three of the four patients; the fourth patient remained clinically stable. The study was conducted by researchers at the University of California, San Francisco (UCSF).

A summary of the trial results were presented Saturday, March 31, at the 2012 European Leukodystrophy Association (ELA) Families/Scientists Meeting in Paris. The findings are being submitted for publication in a peer-reviewed scientific journal.

"The results from this Phase I study are meaningful and important," said study investigator Nalin Gupta, MD, PhD, UCSF associate professor of neurological surgery and pediatrics and chief of pediatric neurological surgery at UCSF Benioff Children's Hospital. "The safety and clinical outcomes a year after transplantation in this Phase I study, combined with durable radiological signals of myelin formation, provide objective evidence of a biological effect of HuCNS-SC transplantation that addresses the fundamental basis of the pathology in the brain of PMD patients. We also wish to recognize the families' contribution to this study. These advances would not be possible without their willingness to participate in this clinical research."

Patients with PMD have a defective gene, which leads to insufficient myelin in the brain. The disease occurs only in males, and those with the most severe form of the disease, connatal PMD, are significantly disabled from birth and usually die, within the first decade of life. The study was the first to test transplantation of neural stem cells as a potential treatment for a myelination disorder. Myelin is the substance that surrounds and insulates nerve cells' communications fibers (also known as axons). Without sufficient myelination, these fibers are unable to properly transmit nerve impulses, leading to a progressive loss of neurological function, and death.

The open-label Phase I trial, conducted between February 2010 and February 2012, enrolled four patients with the connatal form of PMD, between the ages of 14 months and 5 years, and was designed to assess safety and preliminary efficacy of the intervention. The study used magnetic resonance (MR) imaging, commonly employed in other neurological diseases, to explore signs of myelination related to the transplanted neural stem cells. The HuCNS-SC transplants were surgically delivered to multiple sites within the frontal lobes of the brain. Patients also received immunosuppression for nine months following transplantation and underwent intensive follow-up neurological assessments and MR imaging for twelve months following transplantation. A separate four-year observational study will continue to monitor and report the future progress for all four patients.

At the one-year interval, MR imaging showed changes compatible with increased myelination in the region of the transplantation. The MR signs of myelination persisted after the withdrawal of immunosuppression at nine months and were also found to progress over time. The development of new myelin signals is unprecedented in patients with connatal PMD and is consistent with HuCNS-SC engraftment.

"The finding of myelin formation in this first exploratory study is indeed very encouraging," said Stephen Huhn, MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells, Inc. "We believe that the results of this trial provide proof-of-concept and a compelling rationale for the Company to begin planning for a controlled Phase II study in PMD. These results may also have implications for other leukodystrophies, as well as more common myelin disorders including transverse myelitis, multiple sclerosis and periventricular white matter injury seen in Cerebral Palsy. We are very pleased to be working with investigators at UCSF and deeply appreciate the critical research expertise they have dedicated to the trial."

Conference Call

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StemCells, Inc's Milestone Clinical Trial in Pelizaeus-Merzbacher Disease Shows Evidence of Myelination Following ...

ScienceDaily (Apr. 1, 2012) The latest research developments to reprogram scar tissue resulting from myocardial infarction (MI) into viable heart muscle cells, were presented at the Frontiers in CardioVascular Biology (FCVB) 2012 meeting, held 30 March to 1 April at the South Kensington Campus of Imperial College in London.

In a keynote lecture Dr Deepak Srivastava outlined his approach that has been described as a "game changer" with the potential to revolutionise treatment of MI. For the first time at the FCVB meeting, Srivastava presented the results of his latest studies using viral vectors to deliver genes directly into the hearts of adult mice that had experienced an MI. The FCVB meeting was organised by the Council on Basic Cardiovascular Science (CBCS) of the European Society of Cardiology (ESC).

In his original "proof of principle" study, published August 2010 in Cell, Srivastava was able to show that all that was needed for the direct reprogramming of fibroblasts (a major component of scar tissue) into myocytes (heart muscle cells responsible for beating) was the delivery of three genes.

The work , which took place in a Petri dish, was considered groundbreaking since it showed for the first time that unrelated adult cells could be reprogrammed from one cell type to another without having to go all the way back to a stem cell state.

"Our ultimate hope is that, during the acute period following MI, patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the "scar" into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives," explained Srivastava, who is director of the Gladstone Institute of Cardiovascular Disease in San Francisco, US.

Healthy heart tissue is composed of a mixture of several kinds of cells, including cardiomyocytes, which provide beating muscle, and cardiac fibroblasts, that provide architectural support to the myocytes. "When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration," explained Srivastava. Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar.

"The process at first can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later difficulties arise when the fibrotic scar doesn't contract like the muscle it has replaced. Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death," said Srivastava.

One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart. Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury.

"But many hurdles have been encountered including getting cells to integrate with neighbouring cells in the heart, and there have been concerns that residual "rogue" cells could persist with the potential to keep dividing and give rise to tumours," said Srivastava. "Harnessing the vast reservoir of fibroblasts already present in the heart, we felt, could overcome many of these issues. They've the big advantage they're already present in the organ and closely integrated with neighbouring cells."

In the address Srivastava, a paediatric cardiologist, explained how he had first got ahead of the game by "leveraging" knowledge from his work in embryo hearts. Over the past 15 years the focus of Srivastava's lab has been to identify genetic factors responsible for the formation of embryonic hearts.

Link:
Transforming scar tissue into beating hearts: The next instalment