As the field of stem cell based therapies has progressed, there have been numerous questions about the exact way one of the most promising lines of adult stem cells works to repair damaged heart muscle. Although cells obtained from adult bone marrow are proving to be useful to treat heart disease, there has been a major controversy over whether they are true stem cells capable of forming new heart muscle.

Cardiologists at the University of Miami Miller School of Medicine have definitively shown that mesenchymal stem cells from bone marrow do in fact form new heart muscle and blood vessels, leading to major degrees of tissue repair in hearts damaged by a heart attack. Their findings have been published in the August 3 issue of the Proceedings of the National Academy of Sciences.

Under the leadership of Joshua M. Hare, M.D., director of the Interdisciplinary Stem Cell Institute at the Miller School, a team of physician-scientists has demonstrated how allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy. "This evidence that these cells form both heart and blood vessel cells is major proof that the cells are true stem cells and our findings support their ongoing use in clinical trials," says Hare.

Until now scientists have argued whether mesenchymal stem cells work as stem cells or just manufacture growth factors, delivering materials that have a healing effect on the heart. The new research by the Miller School team answers this question. The findings are relevant to patients as these cells are being tested in clinical trials at the Miller School.

Two of the most promising candidates for cell-based therapies are autologous whole bone marrow cells, cells taken from the same person's body, and mesenchymal stem cells (MSCs), which can be taken from several tissue sources. One attractive element of MSCs is their ability to differentiate into a variety of cell types. Ongoing current research includes clinical trials involving MSCs that are both autologous and allogeneic, from another donor.

Hare and his team -- which includes Alan Heldman, M.D., professor of medicine in the Cardiovascular Division at the Miller School, Ian McNiece, Ph.D., director of experimental and clinical cell based therapies at the Interdisciplinary Stem Cell Institute, and Juan Pablo Zambrano, M.D., assistant professor of medicine in the Cardiovascular Division -- have already blazed a trail in the field of stem cell research. They are currently engaged in two clinical trials involving the extraction and injection of mesenchymal stem cells in the treatment of cardiac failure. McNiece says the result of this trial "provides insights into the mechanism of repair by stem cells and validates the potential of these stem cells which we are using in ongoing clinical trials."

For this study, the team of 12 Miller School researchers began with the theory that mesenchymal stem cells have the ability to become implanted and differentiate within infarcted (or scarred) myocardium, damaged heart tissue. Using animal models, the scientists injected mesenchymal stem cells or a placebo into the subjects, used magnetic resonance imaging (MRI) to track the heart's healing, and then employed state-of-the-art microscopy to determine the fate of the injected cells with markers of cardiac, vascular muscle and endothelial lineage.

What the team found was that the MSCs implanted into the infarct areas, differentiated into cardiomyocytes, heart tissue, and persisted within the heart for months following injection. The mesenchymal stem cells also generated new small and large blood vessels. In animals that were given mesenchymal stem cells, there was a reduction in the amount of scar tissue, increased blood flow to the area, and very importantly a restoration of cardiac function.

"What we showed here," says Heldman, "is that the stem cells we injected into the heart muscle actually became part of the new heart tissue; the stem cells turned into both heart muscle cells and blood vessel cells." Hare says "this is the first and definitive demonstration that the cells we are using actually generate new missing cells."

Zambrano says it is gratifying to be able to prove that "stem cell therapy does work, and to contribute to the science of a new era in the management of heart diseases."

In October 2007, Hare was the first in the nation to win approval from the FDA to initiate a clinical trial injecting autologous mesenchymal stem cells for the treatment of heart failure. The randomized, double-blind study has doctors injecting either low-dose MSCs, high-dose MSCs or placebo into patients undergoing heart surgery. In another study, the Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT), Miller School physicians have been the first in the nation to use a spiral shaped catheter to deliver either bone marrow cells, mesenchymal cells or a placebo to patients.

With this latest discovery, the Miller School team of stem cell researchers continues to set themselves apart in this burgeoning field. Hare says the unique feature of the Interdisciplinary Stem Cell Institute program is the parallel relationship between research in the lab and clinical trials. "Our research facilitates the work that we're doing in the human population."

Heldman adds that these findings "add another element to the story of how stem cells work, and why we hope that our unique approach to delivering them to the heart will result in significant benefit for those who have suffered a heart attack."

University of Miami Miller School of Medicine

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