Research reveals master heart cell

By William J. Cromie
Harvard News Office

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.

"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.

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