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Mass. General researchers identify
master cardiac stem cell
Progenitors develop into three types
of heart cells, could be ideal for regenerative studies
BOSTON - November 22, 2006 - Researchers from the Massachusetts
General Hospital (MGH) Cardiovascular
Research Center have discovered what appears to be a master
cardiac stem cell, capable of differentiating into the three major
types of cells that make up the mammalian heart. In their report
appearing in the Dec. 15 issue of the journal Cell and receiving
early online release, the scientists describe identifying these
progenitor cells in mice, cloning single cells from embryonic stem
cells, and showing that these cloned cells can differentiate into
cardiac muscle, smooth muscle or endothelial cells.
"These cells offer new prospects for drug discovery and genetically
based models of human disease. They also give us a new paradigm
for cardiac development, in which a single multipotent cell can
diversify into both muscle and endothelial lineages," says
Kenneth R. Chien, MD, director of the MGH Cardiovascular Research
Center (CVRC) and senior author of the Cell paper. "They
additionally suggest a novel strategy for the regeneration of cardiac
muscle, coronary arterial and pacemaker cells." Chien also
leads the cardiovascular program at the Harvard
Stem Cell Institute, one of the study's supporters.
Several populations of embryonic cells that develop into the heart
and associated structures have previously been indentified. It has
been thought that the three types of cells that make up the heart
itself - the contracting cardiac muscle cells and the smooth muscle
and endothelial cells that make up blood vessels - all develop from
different cellular progenitors. Two major groups of cardiac muscle
progenitors, called the first and second field, have been identified.
In 2005, Chien's team, then at the University of California at San
Diego, described finding a group of cardiac muscle progenitors called
isl1+ cells in heart tissue from newborn rats, mice and humans.
The islet-1 protein, for which isl1+ progenitors are named, is known
to be expressed in cells from the second cardiac field, which generate
the structures on the right side of the heart. The current study
was designed to investigate whether islet-1 expressing cells give
rise to more than just cardiac muscle cells.
In a variety of experiments, the researchers first identified a
small population of embryonic islet-1-expressing cells that can
develop into working cardiac muscle, smooth muscle, pacemaker cells
and the endothelial cells lining the major vessels of the heart
and the coronary arteries. Starting with embryonic stem cells from
mice, they were able to generate these multipotent embryonic isl1+
progenitor cells (MIPCs) - the parental cells that give rise to
the postnatal progenitor cells identified in the 2005 study - and
to clone and expand their population in vitro.
The team's in vivo study of mouse embryos found within primitive
cardiac tissues a small group of cells expressing islet-1 and two
other important proteins called Nkx2.5 and flk1. The researchers
cultured and cloned those cells and found they could differentiate
into all three cardiac cells types, verifying that they were MIPCs.
Expression of the Nkx2.5 and flk1 genes seems to play a role in
the process by which the cells 'decide' their developmental fate.
"We think these are authentic cardiac stem cells that are responsible
for forming the diverse cell types of the heart, although other
cells also contribute to some structures," says Chien. "These
MIPCs may be excellent candidates for cardiac muscle regeneration
studies, without the risk of tumor formation posed by embryonic
stem cells or the limited effectiveness seen in studies using other
cell types.
"It now appears that cardiac cells develop in the same way
that blood cells do, with a master stem cell giving rise to the
entire range of cells. The search is now on for the hormones that
trigger expansion of MIPCs, which would be analogous to the factors
that drive blood formation." Chien was recently named the Sanders
Professor of Basic Science at Harvard Medical School.
The same issue of Cell contains an accompanying
article from the Children's Hospital Boston laboratory of Stuart
Orkin, MD, and the Harvard Stem Cell Institute describing the discovery
in the first cardiac field of progenitor cells expressing the Nkx2.5
protein that can generate both cardiac and smooth muscle cells.
Sean Wu, MD, PhD, the first author of that paper, has recently joined
the MGH-CVRC where he and Chien's team will follow up these seminal
findings, including clarifying any developmental relationship between
the two types of progenitor cells.
Co-first authors of the MGH-based paper are Alessandra Moretti,
PhD, Leslie Caron, PhD, and Atsushi Nakano, MD, of the MGH-CVRC.
Additional co-authors are Jason Lam, PhD, Yibing Qyang, PhD, Lei
Bu, PhD, Silvia Puig, and Karl-Ludwig Laugwitz, MD, PhD, of the
MGH-CVRC; Alexandra Bernshausen, Technical University of Munich,
Germany; and Yunfu Sun and Sylvia Evans, PhD, University of California,
San Diego. Moretti, Lam, and Laugwitz also are associated with Technical
University of Munich. In addition to the Harvard Stem Cell Institute,
the study's supporters include the MGH, the Research Commission
of the European Union, Technical University of Munich, the U.S.
National Heart, Lung and Blood Institute, the French Medical Research
Foundation and the Jean Le Duc Foundation.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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