The outermost layer of the heart wall does more than just protect life's most vital organ — it holds a new type of heart stem cell, according to a pair of studies published in Nature. Two teams — one led by William Pu of the Harvard Stem Cell Institute, in Cambridge, Massachusetts, and the other led by Sylvia Evans of the University of California, San Diego — independently discovered the new stem cells in the epicardium, the protective coating that envelops the heart. The findings hint at potential new routes to mending a broken heart.

Epicardial cells are known to give rise to smooth muscle cells, fibroblasts and the endothelial cells that line coronary blood vessels, but they had never been shown to contribute to cardiac muscle cells, also known as cardiomyocytes. “Before, it wasn't thought that the epicardium could make cardiomyocytes,” says Pu. “But now it appears they have a natural ability” to do so. In fact, “they can turn into all major cell types in the heart,” he says.

Each research group generated mice expressing marker genes to trace the lineages of the epicardial stem cells. Pu's team used the transcription factor Wt1 and showed that Wt1-expressing epicardial cells contribute around 5% of the cardiac muscle cells across all four heart chambers1. Evans' team, however, used a different marker — the Tbox transcription factor, Tbx18. Similar to Pu's results, Evans' team found that Tbx18-expressing epicardial progenitors contributed a substantial portion of the heart muscle tissue2.

The two studies are “simple lineage-tracing studies [that] provide good in vivo evidence for the origin of a subset of cardiomyocytes,” says Deepak Srivastava, of the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco, who was not involved in either study. “They're good for what they are, but they don't tell us about how the progenitors are regulated or how decisions are made” on what fates the cells adopt.

The cells identified by each group showed some subtle differences. Both sets of epicardial precursors differentiated into cardiac and smooth muscle, but although a minority of Pu's Wt1-expressing cells became endothelial cells, Evans' Tbx18-expressing cells did not do so at all. The Tbx18-marked cells did give rise to fibroblasts though — something that Pu's team did not investigate. Srivastava says this difference is probably just a matter of when the markers were expressed within the same pool of cells. So, are both researchers studying the same epicardial heart stem cells? “I think they're the same,” Srivastava says. “They're just marked by different markers.”

The authors themselves take more reserved stances. “You can't say they're the exact same population, but if they're not, there's probably a huge overlap,” says Jody Martin of UC San Diego, a first author on the Evans study. Pu agrees. “I think it's safe to say that there is likely considerable overlap,” he says.

Christine Mummery, of the Leiden University Medical Center in the Netherlands, describes the papers as “very elegant genetic studies,” but cautions that the cardiac muscle–producing cells might not even be epicardial cells at all. “The question is whether they've used only epicardial cells, or, because of the timing and the area they've taken, whether they've included mesenchymal cells [as well].” It remains to be seen if the newfound epicardial cells are truly multipotent precursors, she says. Only a clonal analysis might be able to strike at the heart of the epicardium's potential.