Researchers at Stanford have discovered which type of cell develops into the muscular lining of arteries that feed the heart.
The finding, in mice, as well as the discovery of the molecular signals that govern this transformation, may ultimately lead to human therapies to regrow healthy coronary arteries, the researchers said.
Scientists previously showed that portions of the coronary artery develop from cells on the surface of the heart called epicardial cells. However, the direct progenitors to coronary artery smooth muscle cells, the important component that encases the artery and gives it strength, were not identified.
Through a series of sophisticated techniques, the researchers solved the mystery: They determined that smooth muscle cells in cardiac arteries grew out of a kind of cell called a cardiac pericyte. Perhaps more important, scientists also identified a molecule called notch3 as the signal that governs the conversion of pericytes to cardiovascular smooth muscle cells.
A paper describing the work was published Oct. 19 in eLife.
“What is important about this study is that a precise stem cell technology was used to visualize coronary progenitors among the millions of other cells in the developing heart,” said Irving Weissman, MD, the Virginia and D. K. Ludwig Professor in Clinical Investigation in Cancer Research and the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, who is a co-author of the paper. “This was the key to discovering that pericytes turn into smooth muscle cells in response to increased blood flow.”
Collateral blood vessel formation
Scientists have known very little about how collateral blood vessels form to reroute blood flow around blocked coronary arteries or how to stimulate their development to treat coronary artery disease, said Katharina Sophia Volz, PhD, the lead author of the paper and a researcher at the stem cell institute. Volz pointed out that injured hearts can regenerate tiny blood vessels, but cannot form larger arteries that have the layer of smooth muscle cells required to provide significant blood flow to healing tissues. “Providing the right molecular signals to turn pericytes into smooth muscles cells may promote a transition from tiny blood vessels to true arteries,” she said.
What is important about this study is that a precise stem cell technology was used to visualize coronary progenitors among the millions of other cells in the developing heart.
Kristy Red-Horse, PhD, assistant professor of biology and the paper’s senior author, said she believes that “if we discover the molecular signals that form coronary blood vessels in mouse embryos, we could test their ability to stimulate new vessels in adult mice and potentially use this knowledge to one day repair injured adult human hearts.”
Red-Horse said this process could potentially be replicated in adult mice and then adult humans through the use of these molecular signals. “Since adult human hearts are filled will small capillary blood vessels that are also covered in pericytes, we believe that these can be coaxed to reignite their developmental program and create new coronary arteries,” she said. “Now that we are beginning to really understand the coronary artery developmental program, we have begun studies to reactivate that program in injured hearts and hope to someday use these same methods to help treat coronary artery disease.”
Other Stanford-affiliated co-authors are postdoctoral scholars Daniel Riordan, PhD, and Aruna Poduri, PhD; and graduate students Andrew Jacobs, Heidi Chen, Andrew McKay, Natalie Kofler and Jan Kitajewski.
Support for the research was provided by the National Institutes of Health (grants 4R00HL10579303, U01HL099995 and U01HL099999), the California Institute for Regenerative Medicine, the Virginia and D.K. Ludwig Fund for Cancer Research and the Searle Scholars Program.
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