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Research Finds How Adult Stem Cells Repair Hearts
'Sticky' proteins required to fuse stem cells to cardiac muscle, creating a new cell
Cardiologists are increasingly using adult stem cells in clinical trials to repair hearts following heart attacks, but until now, no one has understood how the therapy actually works. Now, in animal experiments, researchers at The University of Texas institutions in Houston have described how the stem cells fuse with heart muscle cells to create new cells that repopulate the ailing organ.
In a paper posted Feb. 15 at Online First of the journal Circulation Research, "we show the mechanisms responsible for fusion of adult circulating stem cells (human stem cells) with heart muscle cells," said James T. Willerson, M.D., coauthor and president of The University of Texas Health Science Center at Houston and president- elect of the Texas Heart Institute. "We show why they fuse, how they fuse and what the consequences are. The consequences are: when the stem cells and the heart cells come together, a new cell is born. It's a very interesting observation."
Investigators report that this fusion is only possible if two cell adhesion proteins that stick to each other like Velcro are available to attach a stem cell to a heart muscle cell. They showed in cell and mice studies that if either protein is blocked, the two cells don't blend.
The investigators also discovered that these new cells, once fused, divide again in an attempt to produce enough cells to help the heart contract.
Wonderful Ability to Divide Again
"The accepted dogma is that heart cells cannot divide, but we show that fusing stem cells onto muscle cells bestows these cells with a new and wonderful ability to divide again to repair the heart," said the study's lead author Edward T. H. Yeh, M.D., director of the Research Center for Cardiovascular Diseases at The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, which is a part of the UT Health Science Center at Houston. Yeh also is professor and chair of the Department of Cardiology at the UT M. D. Anderson Cancer Center, a faculty member in the UT Graduate School of Biomedical Sciences at Houston, and a member of the Texas Heart Institute.
"It is marvelous that adult stem cells can help heal a heart, and by understanding the mechanisms involved, we may be able to refine and optimize the process," he said.
But there are not enough natural stem cells available in a body to mount an effective repair response to a heart attack, Yeh said, which is why researchers and clinicians are focused on boosting that response. And in the future, given what the researchers also have discovered about how stem cells can build new cells to line blood vessels, it may be possible to "choose to ether augment rebuilding of heart muscle or restoration of blood vessels, depending on what is therapeutically best for the patient."
This study is the latest undertaken in a focused research program conducted by Yeh and a team of researchers at M. D. Anderson, the Texas Heart Institute and the UT Health Science Center to investigate stem cell repair of heart and vascular tissue. In this study, they looked into the mechanism by which stem cells fuse to cardiac myocytes, or muscle cells. In laboratory experiments, they added adult human stem cells to cardiac muscle cells from mice. After 24 hours, some fusion occurred spontaneously - cells were created that had both human and murine protein signatures - but this occurred at a very low rate.
Effects of Heart Attack
They then created conditions that reflect an ongoing heart attack and found that cell fusion increased 10-fold. "It went from 0.2 percent of cells becoming fused to 2 percent," Yeh said.
The researchers noted that as a consequence of the experimental "heart attack," expression of two cell surface adhesion molecules was increased. "The two molecules act like a pair, and stick to each other," Yeh said. "This is the first step to the fusion process."
The researchers tested whether several experimental variations affected the formation of new blood vessels and the differentiation of stem cells into new endothelial cells.
Finally, Yeh et. al. tested the newly fused heart muscle cells to see what they did after they formed. Heart muscle cells do not divide, so the researchers did not know whether the new fused cells were an endpoint in themselves, designed to replace dying cardiac muscle, or whether they could give rise to other new cells. They discovered that fused cells took on some "stemness" - they divided, and continued to do so as long as new tissue is needed, but not long enough to produce a tumor. "In mice, we have found this process can continue for months," Yeh said.
"We show in these animal experiments that human adult stem cells can form new blood vessels and heart muscle cells, and knowing how these two different processes can be blocked could be very useful in determining the relative contribution of each toward heart repair," he said.
The study was funded by a Multidisciplinary Research Program by M. D. Anderson. Co-authors include Sui Zhang, M.D., Ph.D., M. D. Anderson Department of Cardiology, and Elizabeth Shpall, M.D., of the M. D. Anderson Department of Stem Cell Transplantation.