1. Harvard Stem Cell Institute and Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
2. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Harvard Stem Cell Institute, Harvard University and Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA
4. Clinic of Neonatology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany

Correspondence to: William T. Pu^1,2 Correspondence and requests for materials should be addressed to W.T.P. (Email: wpu@enders.tch.harvard.edu).

Abstract

The heart is formed from cardiogenic progenitors expressing the transcription factors Nkx2-5 and Isl1 (refs 1 and 2). These multipotent progenitors give rise to cardiomyocyte, smooth muscle and endothelial cells, the major lineages of the mature heart^{3, 4}. Here we identify a novel cardiogenic precursor marked by expression of the transcription factor Wt1 and located within the epicardium—an epithelial sheet overlying the heart. During normal murine heart development, a subset of these Wt1⁺ precursors differentiated into fully functional cardiomyocytes. Wt1⁺ proepicardial cells arose from progenitors that express Nkx2-5 and Isl1, suggesting that they share a developmental origin with multipotent Nkx2-5⁺ and Isl1⁺ progenitors. These results identify Wt1⁺ epicardial cells as previously unrecognized cardiomyocyte progenitors, and lay the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair.

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