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 System, a Boston-based integrated health care delivery system.
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Cell