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Several studies in recent and upcoming issues of Cell and Developmental Cell, respectively, have identified cardiac stem cells that give rise to an unexpected combination of daughter cells. Taken together, the reports challenge current notions of how the heart develops, and might provide insights for regenerative medicine.

The heart consists of three main types of tissue: cardiac muscle, which does the beating grunt work; vascular smooth muscle, which lines the heart's blood vessels; and endothelial cells, which line the heart itself, as they do with the rest of the circulatory system. Currently, most researchers say that those tissue types derive from distinct embryonic stem cells.

But two papers to be published in the Dec. 15, 2006, issue of Cell challenge that notion.

The first paper, by researchers from Massachusetts General Hospital and Harvard Medical School (Boston), the University of California at San Diego, and the Technical University of Munich (Munich, Germany), reported that in lineage tracing studies, stem cells expressing the marker isl1 gave rise to not only cardiac muscle but also smooth muscle, endothelial, pacemaker, and other nonmuscle cell lineages.

Single cell 'surprise'

"It's a surprise that a single cell can give rise to all of these tissues and structures in the heart," said senior author Kenneth Chien, professor of basic science at Massachusetts General Hospital and Harvard Medical School. "The heart may look more like blood than we thought."

In the second paper, researchers from Children's Hospital, Beth Israel-Deaconess Medical Center, the Dana-Farber Cancer Institute, and Massachusetts General Hospital (all Boston), the University of Southern California (Los Angeles) and the Harvard Stem Cell Institute (Cambridge, Massachusetts), isolated cells from a mouse embryo that expressed a cardiac-specific gene, called Nkx2.5.

While the Nkx2.5 cells spontaneously differentiated primarily into cardiac muscle cells and conduction system cells, some of the precursor cells unexpectedly turned into smooth muscle cells.

The team isolated Nkx2.5 cells derived from embryonic stem cells and found that some of the cells also expressed a second gene, c-kit. It was the c-kit Nkx2.5 cells that had the ability to expand and produce both cardiac muscle and smooth muscle cells from a single cell. The team confirmed that finding by isolating cells in which both genes were active and demonstrating their ability to form both heart muscle types in vivo.

In discussion of their work, the authors wrote that "in summary, we have established the existence of a common myogenic precursor cell that gives rise to both myocardial and smooth muscle lineages," adding that the findings "reveal a hierarchy for myogenic differentiation in vivo and suggest a new developmental paradigm for cardiogenesis, where a single multipotent progenitor cell gives rise to cells of diverse lineages within the heart."

Both Cell papers come on the heels of a November Developmental Cell paper, in which researchers from the Mount Sinai School of Medicine (New York) isolated a stem cell that could produce all three types of heart tissue by using another molecular marker, Flk-1.

'Parental' relationship unclear

The papers have worked out the progeny of their respective stem cells, but the relationship of the parents to each other still is unclear. Chien and colleagues isolated stem cells that are the progenitors of the heart's right chambers, while the cells of the team led by Stuart Orkin of Children's Hospital were slated to become part of the left chambers. Orkin's c-kit and Nkx2.5 expressing cells may be daughters of the Isl1 expressing cells, but the two stem cell types may also be unrelated; both labs are currently working on determining the relationship, or not, between the two stem cells.

While the work is basic research, its implications might be useful in the clinic.

Chien said that "embryonic stem cells are difficult to use for heart regeneration because of the danger of teratomas," which are cancers that result from the uncontrolled growth of embryonic stem cells.

"If we can get around that threat by cloning master cardiovascular stem cells that would be a major advance."

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