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November 22, 2006

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Research reveals how stem cells build a heart

May lead to repair, regeneration of broken hearts

By William J. Cromie
Harvard News Office

Kenneth Chien
Kenneth Chien and his colleagues have uncovered new information about the development of your heart. (Photo courtesy of the Harvard Stem Cell Institute)

Master cells that give rise to the three main cell types in a human heart have been discovered by Harvard Stem Cell Institute scientists working independently at two Harvard-affiliated hospitals. Together they found that a single progenitor stem cell differentiates into cells that cause a heart to beat, that make up its internal surface, and form its blood vessels.

The master cells arise during an early stage of embryo growth. As-yet-undiscovered signals then stimulate them to form the main building blocks of the heart, the first identifiable organ in the development of human life. Once started, that life-sustaining muscular pump beats more than 2,500 million times during an average lifetime.

The Harvard research teams tracked the entire process in mouse embryo cells as they grew in glass lab dishes.

The newly identified progenitor cells "offer new prospects for drug discovery and suggest a novel strategy for regeneration of cardiovascular [heart and blood vessel] tissue," says Kenneth Chien, director of both the Harvard Stem Cell Institute's cardiovascular disease program and Massachusetts General Hospital's center for cardiac research. Until now, it was believed that the three sets of heart cells developed from separate ancestors. "Now we have a new model for heart development in which a single multipotent cell can diversify into three lineages," Chien notes.

Stuart Orkin, Sean Wu
Stuart Orkin (left) and Sean Wu are part of a team who discovered a master cell that gives rise to the three main types of cells in the human heart. (Staff photo Rose Lincoln/Harvard News Office)

"The mechanism of cardiogenesis [heart formation] has fascinated biologists for two centuries," points out Stuart Orkin, a Harvard Stem Cell Institute researcher who led a separate team at Children's Hospital Boston. "Despite beliefs that the different cells had distinct origins, recent animal experiments have suggested that a large proportion of cells in the mature heart share a common ancestry. To investigate this, we isolated cardiac progenitor cells from early stage mouse embryos and followed their differentiation. Expectedly, the majority of these cells differentiated spontaneously into muscle cells that expand and contract the heart's chambers. But, surprisingly, a subset of the cells adapted a smooth muscle cell fate." This accounted for two of the three major building blocks coming from a single source. The third cell type was identified by Chien's team at Mass General Hospital.

Rebuilding damaged hearts

Orkin and Chien, of course, did not do all this by themselves. Work on this scale requires a team approach. Two reports in the December issue of the journal Cell lists those who played a role in changing how biologists think about the way nature makes a heart. An online version of their efforts was released on Nov. 22. Sean Wu, first author of the report by the Orkin team, now leads a research group that will work with Chien's team and follow up these significant discoveries at Mass General's Cardiovascular Research Center.

Things got started in 2005 when a team led by Chien found the same heart stem cells in newborn rats, mice, and humans. These cells were known to be involved in constructing tissues on the right side of the heart. Pursuing this lead, Chien and his group were eventually able to generate multipotent master cells from mouse embryos, which parent all three cell types.

"We think that these are authentic cardiac stem cells that are responsible for forming the diverse cell types of the heart, although other cells contribute to some structures," Chien notes.

Meanwhile, just blocks away at Children's Hospital, Orkin, Wu, and their team independently pursued the same goal. They uncovered the progenitor cells that morph into muscle cells that move blood and line the chambers of the left side of the heart. In Wu's words, "We both have found the rare population of master cells that gives rise to the building blocks that form a functional heart."

Together, they provide new information that will lead to the rewriting of all books about the development of the mammalian heart and, eventually, to ways in which broken human hearts can be mended and regenerated. The results, Chien says, "suggest an alternative strategy for achieving the regeneration of distinct heart components that are affected in diverse forms of degenerative heart disease."

Reinvigorating failing hearts with stem cells has been proposed many times before. But animal experiments reveal that stem cells taken directly from embryos can grow without proper control and cause tumors. Stem cells that have already undergone development into heart progenitor cells are less likely to end up in tumors, researchers believe.

The new experiments indicate that master cells can be cloned to create a supply of spare parts for the heart that are free of the problem of tumor formation. Medical experts have dreamed about having a supply of cells that might be coaxed into becoming working heart muscles, pacemakers, and blood vessels as undamaged as those in healthy newborns. Maybe those dreams are now closer to coming true.


Copyright 2006 by the President and Fellows of Harvard College