The findings, published in the July 29 issue of Circulation Research, a journal of the American Heart Association, address an area that has been of enormous interest to cardiologists since the first suggestion that bone marrow-derived mesenchymal stem cells regenerate heart muscle damaged by a myocardial infarction (heart attack). Joshua M. Hare, M.D., director of the Interdisciplinary Stem Cell Institute at the Miller School, led the discovery which settles several major controversies in the field and shows that the stem cells used can restore heart function back to normal very rapidly after heart attack.
The stem cell field has been plagued by a controversy surrounding exactly how bone marrow cells repair damaged hearts. In this study Hare’s group shows that the cells not only turn into new heart muscle themselves (acting as true stem cells) but also stimulate the body’s own cardiac stem cells to go into overdrive to contribute to the repair process. These findings settle one of the most controversial areas of medicine – why the heart’s own stem cells are not able to fully repair heart damage. By showing that the MSCs can stimulate the heart’s own cells, the researchers have shown that in fact the body can repair itself if given the right kind of help.
The research is of particular importance as these cells have already been tested for safety in patients with heart attack and are undergoing additional testing right now for patients with heart failure.
This team hypothesized that MSCs encourage cardiac repair by stimulating cardiac stem cells (which are already present in the adult heart, and appear to be precursor cells to heart muscle) both to multiply and to differentiate into the hard-working heart muscle cells called cardiac myocytes, which then begin to “beat” or contract. Working with animal models, the researchers induced a heart attack (myocardial infarction). Three days later, the hearts were treated by injection directly into the damaged heart muscle, either with MSCs, or with the fluid medium containing MSC-secreted chemicals but no cells, or with a placebo.
The University of Miami team found that MSCs “facilitate substantial cardiac recovery,” producing both cardiac myocytes and blood vessel structures in two ways. Some of the MSCs differentiated into cardiac cells. Secondly, the MSCs appeared to cause cardiac stem cells to multiply and to differentiate themselves into cardiac cells.
“This shifts the paradigm of stem cell research,” says Hare. “For the first time, we’ve been able to demonstrate the exact mechanism of how mesenchymal stem cells stimulate the growth of new cardiac cells. The findings have implications for the entire field of regenerative medicine and show that the optimal therapies involve cells working together, rather than using only single cell types.”
In the animals that were treated with mesenchymal stem cells, there was a 20-fold increase in cardiac stem cells. When examined in vitro, MSCs stimulated cardiac stem cell proliferation into enriched populations of adult cardioblasts.
Alan W. Heldman, M.D., a professor of medicine and member of the Interdisciplinary Stem Cell Institute, was the interventional cardiologist who performed the catheter-based injections into the heart muscle. Heldman notes that this study “points out a totally new and intriguing aspect of working with this stem cell line.” The data indicate that MSCs generate new cardiomyocytes in the first 24 hours. Additionally, they stimulate a series of secondary responses that cause substantial amounts of adult and immature cardiomyocytes to proliferate and replenish the damaged regions of the heart.
“This points to a long-term effect that can pave the way for future therapies,” Heldman said. “We have known for several years that there is a measurable but very low rate of cell turnover in the adult heart; it seems that stem cell therapy may harness that natural phenomenon and accelerate it to the point that it becomes clinically important as a potential therapy.”
“As a clinician and researcher, this is very encouraging,” says Juan Pablo Zambrano, M.D., associate professor of medicine in the Cardiovascular Division. “This study and previous research continues to bear out the possibilities of generating cardiac repair using this stem cell line.”
“We continue to see evidence that mesenchymal stem cells have the ability to spur new cardiac muscle growth,” says Ian K. McNiece, Ph.D., professor of medicine and director of experimental and clinical therapies at the Interdisciplinary Stem Cell Institute.
Hare says this study, which was funded by grants from the National Heart, Lung, and Blood Institute, “reinforces our hypothesis that mesenchymal stem cells have enormous potential as a cell-based therapy for cardiac patients. The findings of this study support our ongoing program of developing this therapy for use in patients.”