BIOTECHNOLOGY

 


Osiris Therapeutics, Inc.

Growing Adult Stem Cells into Heart Muscle

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Heart disease is the number one cause of death and disability in the United States, afflicting more than 7 million people and incurring medical costs of more than $100 billion annually. Once the heart muscle is damaged, decline is inevitable without costly and risky surgery or lifelong drug therapies. Cardiac research has turned to biotechnology for promising alternatives to conventional heart disease treatment.

By the late 1990s, Osiris Therapeutics, Inc., a small tissue engineering company, had done extensive pioneering work with mesenchymal stem cells (MSCs), which are found in bone marrow and can be harvested from adult donors. The company was growing these cells into bone, cartilage, tendon, fat, and skeletal muscle tissue in the laboratory and held several patents on MSC technology. The company thought it could also develop MSCs for heart therapy. Osiris needed support for the next steps, but was unable to interest outside investors in this risky venture and did not have adequate revenue to fund the research itself. Osiris applied to the Advanced Technology Program (ATP) under the 1997 "Tissue Engineering" focused program and received an award for a project that began in March 1998.

After extensive research, Osiris demonstrated that human MSCs would grow into heart muscle without being cultured outside the body. This attribute could ultimately save lives by allowing intervention immediately after a heart attack and could improve and lengthen the lives of people with congestive heart failure. These results accelerated research, and by the time the project ended in 2001, Osiris was seeking investors to help fund clinical trials. The company entered into a partnership with Boston Scientific Corporation, a leading medical device manufacturer. In 2003, the two companies announced that they would commercialize MSCs for heart therapy. Their first product, Provacel, entered human clinical testing in March 2005 for approval by the Food and Drug Administration.

Osiris researchers have published numerous articles and have made presentations on the project’s outgrowth at conferences on heart disease. Investors continue to show interest in this promising therapy. In 2005, Osiris attracted $29 million in venture capital and ranked fourth in venture capital attraction in Maryland. In August 2006, Osiris conducted an initial public offering that resulted in a capitalization of approximately $300 million, making it the second-largest public stem cell company in the world.

 COMPOSITE PERFORMANCE SCORE
                  (based on a four star rating)
                   * * *

Research and data for Status Report 97-07-0049 were collected during January – February 2006.

 

 

Adult Bone Marrow Stem Cells Hold Promise

Heart disease, the leading cause of death and disability in the United States, afflicts more than 7 million people in the United States. More than 300,000 Americans die annually from congestive heart failure, because cardiac

 

muscle has little or no capacity for self-repair. Moreover, heart disease costs Americans more than any other disease; more than $100 billion annually in medical costs alone, according to the American Heart Association. After a heart attack, the cells of the heart muscle die, and muscle wall is replaced with weak scar tissue that


 

cannot contract. Conventional treatments are unable to repair this muscle damage. People who have had a heart attack have a sudden death rate up to six times greater than the general population, and about two-thirds of heart attack patients never completely recover.

In the late 1990s, medical researchers were looking at human mesenchymal stem cells (MSCs), or marrow stromal cells, for a variety of therapies. These cells can differentiate (change from a generalized to a specialized cell) into bone, cartilage, tendon, fat, and skeletal muscle tissue. In particular, researchers’ attention was focused on bone marrow stem cells, which can be harvested from adult donors through a simple procedure under local anesthetic.

People who have had a heart attack have a sudden death rate up to six times greater than the general population, and about two-thirds of heart attack patients never completely recover.

Osiris Therapeutics, Inc. and its subcontractor, Johns Hopkins University (JHU), theorized that MSCs could differentiate into cardiac muscle and could restore function to damaged heart tissue. The company knew how the MSCs behaved and had a method to produce them; furthermore, it held 15 patents related to MSC research and was preparing MSCs to treat bone and cartilage injuries. The company also had developed effective methods to differentiate the cells outside the body, but had not been able to grow the cells into muscle.

Other companies and research labs were using human heart muscle stem cells, but Osiris was the first to use an isolated, purified adult cell that might differentiate into other cells. If successful, Osiris’ experiments could yield a more plentiful source of cells for heart repair. This would effectively revolutionize the health care industry by reducing medical costs, improving the well-being of patients with heart conditions, and providing an alternative to the chronic shortage of donor hearts for transplants. The U.S. market for the proposed technology was estimated at $2 billion in 1998. The potential benefit from adult stem cell therapy is that fully functional cells

 

incorporated into the diseased tissue would result in treatment that was better than organ transplants, heart bypass surgery, or drugs. Treatment would avoid expensive and risky immune-suppression drugs, and rather than simply repairing existing damaged muscle, the patient’s heart would grow new, healthy muscle tissue.

When Osiris began work on this project in the late 1990s, investors were funding the development of orthopedic therapies, but not the higher risk cardiac work. As a small start-up company, Osiris could not allocate sufficient money to a project with such high technical risk. In 1997, the company applied to ATP under the “Tissue Engineering” focused program and received a cost-shared award for a three-year project that began in 1998.

The Osiris researchers planned to harvest MSCs and treat them with various media and agents that cause them to differentiate into, or adopt the characteristics and function of, heart muscle. The researchers were also interested in determining whether MSCs would differentiate into heart muscle in the body after they were directly implanted in animals’ hearts. In contrast to typical tissue-engineering projects, where researchers grow tissue in the lab and then introduce it to the body, this approach would have the entire muscle-formation process take place within the body. The MSCs would be tested in both normal and damaged animal cardiac muscle. The researchers hypothesized that they would need to trigger the MSCs biologically, electrically, or mechanically before the MSCs would function like normal tissue.

Challenge Lies in Restoring Function

Osiris sought to develop a therapy to treat the loss of heart cells and muscle function. The overall goal of the project was to implant MSCs into the site of a myocardial infarction, or heart attack, where ordinary heart muscle cells have been damaged. They had to determine whether bone marrow MSCs would migrate to damaged heart muscle, generate functional heart muscle, and improve the muscle's ability to contract. They faced several technical challenges:

·         Finding the conditions that induce adult stem cells to mature into cardiac muscle

 

 

·         Validating the maturation into cardiac cells in culture or in the body

·         Showing restored function to damaged heart muscle

Osiris defined four sequential tasks to overcome these challenges:

·         Convert MSCs to heart muscle cells in vitro (outside the body) by culturing them with other cells or growth factors

·         Seed the heart muscle with new MSCs in small animals and observe whether MSCs became cardiac cells

·         Create new heart muscle tissue in rats and dogs

·         Evaluate how well cells integrate into the existing heart muscle

Business and Technical Surprises Provide
New Opportunities

In the first task of culturing MSCs in a test tube, only a few cells differentiated. Initial transplantation experiments proved satisfactory but not excellent. The team then proceeded to explore combinations of growth factors, gene transfer by introducing gene carriers into cells, and culturing of MSCs with cells that could promote growth into heart muscle. They planned to transplant the newly grown cells into various animals.

During this technically challenging phase, Osiris' major source of research and development funding, Novartis, withdrew its support as it redefined its strategy away from several research and development ventures. This loss forced Osiris to concentrate on other near-term projects, a decision that put the ATP-funded project in jeopardy because of its very high technical risk and the time it would take to achieve clinical application.

Osiris brought in subcontractor JHU for its surgical expertise with heart surgery and blood vessel repair. Dr. William Baumgartner and his team in the Division of Cardiac Surgery conducted tests of Osiris’ adult stem cells taken from a pig's bone marrow. When injected directly into the same pig’s heart muscle after partial tissue death from loss of blood (infarction) or constriction

 

of a blood vessel (ischemia), the cells restored the heart's function to better approximate its original condition. At the same time, Osiris’s studies were revealing that it was not necessary to grow muscle cells outside the heart because the cells developed characteristics similar to heart muscle cells when placed in heart muscle. Osiris tested this hypothesis in its heart repair model to show that the heart tissue did not reject the donor cells, as frequently happens with organ transplants.

The overall goal of the project was to implant mesenchymal stem cells (MSCs) into the site
of a heart attack, where ordinary heart muscle cells have been damaged.

Concurrently, Osiris research discovered the MSCs’ ability to suppress the body’s rejection response to “non-self” tissues, that is, donor tissue from other individuals. Osiris tested this hypothesis in its heart repair model to show that the heart tissue did not reject the donor cells, as frequently happens with organ transplants. This was one of the most promising findings of the project, because it meant that Osiris could produce enough MSCs from one healthy bone marrow donor to treat potentially hundreds of unrelated patients. Osiris reproduced the results of a small rodent heart attack model in swine and produced nearly full recovery of muscle function within two months of a heart attack. Osiris researchers said that dead, non-functioning scar tissue was minimized, leaving only a small trace of the heart attack. Based on this success, the project expanded to study treatments that would be effective at the time of the heart attack, avoiding treatment delays due to culture expansion time. As papers were published, other companies began to show interest in partnering with Osiris.

The team next tested human MSCs by placing them in a normal adult mouse heart to see if the MSCs would respond to unknown signals present in the tissue and whether those MSCs would show signs of differentiation once in the heart. By the end of 2000, Osiris had demonstrated that MSCs:

·         Would grow plentifully if injected directly into the animal’s heart.


 

·         Could be injected at the time of injury, not two weeks later as originally believed.

·         Could be grafted from one type of animal into another type of animal as successfully as the subject’s own cells.

These results suggested that this therapy could be expanded to treat heart attacks as they take place, rather than waiting two weeks. Team researchers began to present their dramatic and promising project results at conferences around the country.

By the final year of the project, the results had greatly exceeded the expectations the researchers had at the project’s outset. At project close in 2001, the team was prepared to submit an application for Food and Drug Administration (FDA) approval for injection of MSCs at the time of heart muscle injury.

Osiris Forms Strategic Alliance to Commercialize ATP-Funded Technology     

Osiris, which held exclusive rights to the MSC technology, entered into a partnership with Boston Scientific Corporation in 2001, after the end of ATP funding. At the time, Boston Scientific was a developer, manufacturer, and marketer of medical devices and the second-largest manufacturer of cardiac stents in the United States. In 2003, Boston Scientific and Osiris announced that they had formed a strategic alliance to develop and commercialize cardiovascular therapies using MSCs. The alliance gave Boston Scientific an equity investment and the worldwide rights to market MSC-based products for use in cardiovascular therapy. Boston Scientific's partnership with Osiris was seen as validating the technology and paving the way to commercialization.

The alliance partners produced Provacel, a formulation of MSCs that could be easily administered intravenously to patients to repair damaged heart tissue. They also developed a direct-injection treatment using a catheter designed by Boston Scientific to introduce the cells into the affected area of the heart. Under the terms of the alliance, Osiris would produce the MSCs and Boston Scientific would sell both the cells and the injection catheters globally. Osiris would mass-produce the MSCs, then freeze them and ship them to hospitals for storage until needed.

 

Although intravenous treatment may not be as effective as direct delivery by catheter,  researchers are testing that method because it is simpler. It is also unclear how or why the adult stem cells develop into new and healthy heart tissue or how long their healing effects last. Since humans are different from other animals, the long-term results in pigs may not accurately predict the results in humans (see Figure 1).

Untreated Control

Provacel Treated

 

Figure 1.  The circled region denotes extent of scar in each image. Dense scar formation and wall thinning is seen in control hearts. In contrast, scar is limited and ventricle wall thick in hearts of MSC-treated animals.  Source: Osiris Therapeutics, Inc.

The Heart Failure Society conferred its Young Investigator Award for Senior Research Scientists on a member of the Osiris team in 2004 for the work on rat heart muscle. Human clinical trials to demonstrate Provacel’s safety and effectiveness to the FDA began in March 2005. By April 2006, Osiris announced that the trials had passed two safety milestones, permitting the company to administer higher doses of the cell-based therapeutic to the 53 patients enrolled in the study. However, the three stages of FDA approval will take another five years at minimum, according to those familiar with tissue engineering trials.

By the final year of the project, the results
had greatly exceeded the expectations
of the researchers.

If proven successful, Provacel will “represent a major advancement in the treatment of heart attack patients,“ said Dr. Joshua Hare, JHU Director of Heart Failure and Cardiac Transplantation and the first investigator to treat patients in the study. “The universal nature of the product combined with its ease of use would make it possible for cardiologists to treat patients in almost any setting.” 


 

The success of its heart therapy led Osiris to apply for another ATP award (98-01-0056) for bone regeneration. The company developed additional products based on MSCs, including the following:

·         Autoimmune program to support bone marrow transplantation after chemotherapy or radiation therapy

·         Orthopedic application to regenerate meniscal cartilage tissue following surgery for knee injuries

·         Therapy to repair damage from Crohn’s disease

In 2005, Osiris attracted $29 million in venture capital, which was the fourth-highest in venture capital attraction in Maryland. In August 2006, Osiris conducted an initial public offering that garnered approximately $300 million and made the firm the world’s second-largest public company in stem cell technology.

Conclusion

Osiris Therapeutics applied to ATP’s “Tissue Engineering” focused program in 1997 for a three-year award to grow adult mesenchymal stem cells (MSCs) into heart muscle. The company already held several patents on MSCs and had had success growing other kinds of tissue, but had not grown MSCs into heart muscle. The potential benefits from Osiris’ proposed heart disease treatment would be significant. Heart disease is the number one killer in the United States and costs the nation tens of billions in medical care, lost earning power, and decreased quality of life. The ATP cost-shared project began in 1998.

Human clinical trials to demonstrate
Provacel’s safety and effectiveness to the FDA began in March 2005.

Early tasks yielded surprises that advanced the project and, ultimately, these results led a major medical devices manufacturer, Boston Scientific Corporation, to partner with Osiris in producing the first MSC heart therapy product, Provacel. This cell-based therapeutic can be injected directly or intravenously into a patient’s

 

heart, where it will grow muscle tissue that the body does not reject. The therapy entered human clinical trials in 2005 and passed the first two tests for safety and efficacy. By April 2006, the company had enrolled 53 patients in trials of higher dosages of Provacel. Osiris is actively pursuing MSC therapy for other areas and has attracted significant capital. The company has published articles and made numerous presentations at professional conferences. One member of the research team won an award in 2004 from the Heart Failure Society. In August 2006, the company’s initial public offering netted $300 million and made Osiris the second-largest public stem cell company in the world. The outlook for this technology is strong.

 


PROJECT HIGHLIGHTS
Osiris Therapeutics, Inc.

Project Title: Growing Adult Stem Cells into Heart Muscle (Cardiac Muscle Regeneration Using Mesenchymal Stem Cells)

Project: To demonstrate that mesenchymal stem cells (MSCs) from bone marrow can differentiate into cardiac muscle and restore function to damaged heart tissue, potentially enabling a significant new cell-replacement therapy for heart patients.

Duration: 3/1/1998 - 2/28/2001
ATP Number: 97-07-0049

Funding (in thousands):
 
ATP Final Cost                $1,870    42.7%
Participant Final Cost        2,505    57.2%
Total                                $4,375

Accomplishments: With ATP funding, Osiris met their proposed technical goals, and their advancements have led to therapeutic applications well beyond their original expectations. The company accomplished the following:

·          Showed that MSC-based therapy could contribute to muscle cell growth in damaged heart muscle that led to improvement in function

·          Demonstrated in animal tests that this therapy could be administered with cells from other donors as well as the subject’s own cells

·          Discovered that heart attack treatment with MSCs could begin immediately at the time of injury rather than weeks later

·          Was awarded the Heart Failure Society's 2004 Young Investigator Award for Senior Research Scientists for one team member's work on damaged heart muscle in rats

Commercialization Status: After ATP funding ended, Boston Scientific Corporation and Osiris jointly developed Provacel, a drug therapy that can be infused intravenously or injected into the heart to form muscle tissue. As of 2006 the product is in the first of three stages of human clinical testing required by the Food and Drug Administration (FDA) for approval for sale on the U.S. market. Approval and launch are five to seven years away at minimum, according to observers. In May 2006, Osiris filed for an initial public offering with the Securities and Exchange Commission and raised $300 million.

 

Outlook: The outlook for the MSC-based therapy is strong. The research yielded better-than-expected results, leading to a therapeutic application that promises to heal heart muscle damaged by heart attack and congestive heart failure. If approved by the FDA, Provacel, the first product to emerge from the ATP-funded project, is likely to bring immense benefit to society by improving the survivability and the longevity of heart disease patients. 

Composite Performance Score: * * *

Number of Employees: 96 at project start; 80 as of February 2007.

Focused Program: Tissue Engineering, 1997

Company:
Osiris Therapeutics, Inc.

2001 Aliceanna Street

Baltimore, MD 21231-3043

 

Contact: Randell G. Young

Phone: (410) 522-5005

 

Subcontractors:

 

·          Johns Hopkins University
School of Medicine
Baltimore, MD

 

·          Barry Burns
University of Florida School of Medicine Gainesville, FL

 

Publications:

 

·          Vogel, Gretchen. “Harnessing the Power of Stem Cells.” Science, pp. 1,432-1,434, March 5, 1999.

·          Pittenger, M.F., A. Mackay, et al. ”Multilineage Potential of Adult Human Mesenchymal Stem Cells.” Science, 284, pp. 143-147, April 1999.

·          Mosca, J.D., J.K. Hendricks, D. Buyaner, et al. "Mesenchymal stem cells as vehicles for gene delivery." Clinical Orthopaedics and Related Research, 379, pp. S71-S90, Suppl. S, October 2000.

·          Toma, C., M.F. Pittenger, B.J. Byrne, et al. "Adult human mesenchymal stem cells differentiate to a striated muscle phenotype following arterial delivery to the murine heart." Circulation, 102 (18), p. 3301 Suppl. S, October 31, 2000.

PROJECT HIGHLIGHTS
Osiris Therapeutics, Inc.

·          "Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep." Nature Medicine, 6 (11), pp. 1,282-1,286, November 2000.

·          Toma, C., P.D. Kessler, B.J. Byrne, et al. "Human mesenchymal stem cells differentiate to a striated muscle phenotype in the murine heart." Molecular Biology of the Cell, 11, p. 2,116 Suppl. S, December 2000.

·          Catalin, T., M.F. Pittenger, B.J. Byrne, K. Cahill, and P.D. Kessler. “Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte-like Phenotype in the Murine Heart.” Circulation, 2001.

·          Shake, J., P. Gruber, W. Baumgartner, et al. “In-vivo MSC Grafting in Swine Myocardial Infarct Model: Molecular and Physiological Consequences.” Annals of Thoracic Surgery, 2001.

·          Bell, Julie. "Osiris is banking on universal cell." The Baltimore Sun, 1C, January 3, 2001.

·          Caparrelli, D.J., S.M. Cattaneo, J.G. Shake, et al. "Cellular cardiomyoplasty with allogeneic mesenchymal Stem cells results in improved cardiac performance in a swine model of myocardial infarction." Circulation, 104, 17, p. 2,833, Suppl. S, October 23, 2001.

·          Devine, S.M., S. Peter, B.J.Martin, et al. "Mesenchymal stem cells: Stealth and suppression." Cancer Journal, 7, pp. S76-S82, Suppl. 2, November-December 2001.

·          Toma, C., M.F. Pittenger, K.S. Cahill, B.J. Byrne, and P.D. Kessler. "Adult human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the murine heart." Circulation, 105, pp. 93-98, 2002.

·          Shake, J.G., P.J. Gruber, W.A. Baumgartner, et al. "Mesenchymal stem cell implantation in a swine myocardial infarct model: Engraftment and functional effects." Annals of Thoracic Surgery, 73(6) pp. 1919-1925, June 2002.

·          Pittenger, M., P. Vanguri, D. Simonetti, and R. Young. "Adult mesenchymal stem cells: potential for muscle and tendon regeneration and use in gene therapy." J. Musculoskelet Neuronal Interact, 2, 4, pp. 309-320, June 2002.

 

·          Barry F.P. "Biology and clinical applications of mesenchymal stem cells." Birth Defects Res C Embryo Today, 69, 3, pp. 250-256, August 2003.

·          Hill, J.M., A.J. Dick, V.K. Raman, et al. "Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells." Circulation, 108, 8, pp. 1009-1014, August 26, 2003

·          Chin, B.B., Y. Nakamoto, J.W.M. Bulte, et al. “In-111 oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction.” Nuclear Medicine Communications, 24, 11, pp. 1149-1154, November 2003.

·          Chapel, A., J.M. Bertho, M. Bensidhoum, et al. "Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome." Journal of Gene Medicine, 5, 12, pp. 1028-1038, December 2003.

·          Barry, F.P., and J.M. Murphy. "Mesenchymal stem cells: clinical applications and biological characterization." International Journal of Biochemistry & Cell Biology, 36, 4, pp. 568-584 April 2004.

·          Karmarkar, P.V., D.L. Kraitchman, I. Izbudak, et al. "MR-trackable intramyrocardial injection catheter." Magnetic Resonance In Medicine, 51, 6, pp. 1163-1172, June 2004.

·          Pittenger, M.F. and B.J. Martin. "Mesenchymal stem cells and their potential as cardiac therapeutics." Circulation Research, 95, 1, pp. 9-20, July 9, 2004.

·          Silva, G.V., S. Litovsky, J.A.R. Assad, et al. "Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model." Circulation, 111, 2, pp. 150-156, January 18, 2005.

·          Le Blanc, K., and M.F. Pittenger. "Mesenchymal stem cells: progress toward promise." Cytotherapy, 7, 1, pp. 36-45, March 2005.

·          "Osiris Therapeutics, Inc.; Trial studying adult mesenchymal stem cells on heart attack victims announced." Biotech Week, p. 821, April 27, 2005.

·          Amado, L.C., A.P. Saliaris, K.H. Schuleri, et al. "Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction." Proceedings of the National Academy of Sciences, 102, 32, pp. 11474-11479, August 9, 2005.

PROJECT HIGHLIGHTS
Osiris Therapeutics, Inc.

·          Kraitchman, D.L., M. Tatsumi, W.D. Gilson, et al.  "Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction." Circulation, 112, 10, pp. 1451-1461, September 6, 2005.

·          Saliaris, A.P., L.C. Amado, K.H. Schuleri, et al. "Feridex labeling of allogeneic mesenchymal stem cells does not impair cardiac regenerative capacity." Circulation, 112, 17, p. U707-U707 3038, Suppl. 2, October 25, 2005.

·          Bacchus, Joe. "MD-based Osiris Therapeutics researching stem cell treatment for cardiac damage." The Daily Record (Baltimore, MD), November 7, 2005.

·          "Osiris Therapeutics, Inc. Safety milestone reached in stem cell clinical trial for cardiac patients." Biotech Week, p. 748, December 7, 2005.

·          Kleiner G.I., P. Gordon, J. Kuluz, G. McLaughlin, R. Pahwa, C. Ricordi, N. Kenyon, and R. Monroy. "Successful treatment of refractory GVHD in an infant with malignant osteopetrosis with a human adult mesenchymal stem cell based drug." Biology of Blood and Marrow Transplantation, 12, 2, pp. 66-66 188, Suppl. 1, February 2006.

·          Lehrke S., D.J. Durand, R. Mazhari, J.M. Zimmet, D. Bedja, R.M. Saraiva, J.O. Kuang, R. Young, B.J. Martin, K.L. Gabrielson, R. Mills, and J.M. Hare. "Aging impairs the beneficial effects of intravenous infusion of mesenchymal stem cells on post-myocardial infarction remodeling." Journal of the American College of Cardiology, 47, 4, p. 192A-192A Suppl. A, February 21, 2006.

·          Arnst, Catherine. “Heart, Heal Thyself?“ Business Week Online, p. 3-3, March 6, 2006.

·          “Osiris completes enrollment in stem cell trial to treat cardiac disease.” Chemical Business Newsbase, April 5, 2006.

·          “Osiris Therapeutics Inc. completes enrollment in trial evaluating drug candidate Provacel.” Daily Record (Baltimore, MD), April 6, 2006.

·          “Osiris completes enrollment in stem cell trial to treat cardiac disease.” Transplant News, 16, no. 7, April 17, 2006.

Presentations:

 

·          Martin, B.J., G. Senechal, and M.F. Pittenger. “Implantation and myogenic differentiation of human mesenchymal stem cells (hMSC) in infarcted rat myocardium.” Heart Failure Society, 1999

·          Senechal, G., B.J.Martin, and M.F. Pittenger. Implantation and myogenic differentiation of human mesenchymal stem cells (hMSC) in athymic rat myocardium.” Heart Failure Society, 1999

·          Hu, H., A. Mackay, G. Senechal, and M.F. Pittenger. “Human adult stem cells differentiate to a myogenic phenotype.”  American Heart Association Developmental Cardiology Meeting, April 1999

·          Hu, H., A. Mackay, and M.F. Pittenger. “Myogenic Differentiation of Human Adult Mesenchymal Stem Cells.” American Heart Association, 1999.

·          Martin, B.J., G. Senechal, and M.F. Pittenger. “Implantation and Myogenic Differentiation of hMSCs in Infarcted Rat Myocardium.” American Heart Association, 1999.

·          Toma, C., B. Byrne, et al. “Efficient myogenic conversion of human MSCs expression of myoD.” American Heart Association, 1999.

·          Pittenger, M.F. “Adult Stem Cells for Cardiac Muscle Regeneration.” CHI Tissue Engineering Conference, 1999.

·          Pittenger, M.F. “Adult Stem Cells for Muscle Implantation.” Muscular Dystrophy Association Stem Cell Workshop. Muscular Dystrophy Workshop, May 2005.

·          Martin, B., J. Meyers, J. Shake, et al. “MSC Implantation in Infarcted Swine Myocardium.” American Cellular Biology Meeting, 2000.

·          Meyer, J., and B. Martin. “Allogeneic MSC Engraftment in the Infarcted Rate Heart: Timing and Route of Delivery.” American Heart Association, 2001.

·          Capparelli, D., S. Cattanes, E. Flynn, et al. “Cellular Cardiomyoplasty with Allogeneic MSCs Results in Improved Performance in a Swine Model of Cardiac Infarction, American Heart Association, 2001.

·          Hare, Joshua, and Alan Heldman. American Heart Association's Scientific Sessions, November 2004.

Research and data for Status Report 97-07-0049 were collected during January – February 2006.