Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart

Abstract

Knowledge of the nature of cardiac progenitor cells is important for an understanding of the development of heart diseases, and as a potential route to regenerative therapy using stem cells. Two groups now report previously unknown cardiac myocyte lineages isolated from the proepicardium of the mouse. Cai et al. identify a population of progenitor cells that express the transcription factor Tbx18, and Zhou et al. identify cells marked by the transcription factor Wt1. Both types of progenitor are pluripotent, capable of producing several different classes of heart cell, making them promising candidates for use in cardiac repair. In this paper, a new type of cardiac progenitor, marked by the transcription factor Wt1, is shown to reside in the proepicardium and epicardium. It is shown that during normal heart development, a subset of Wt1+ precursors differentiated into fully functional cardiomyocytes, and they arise from Wt1 progenitors that express Nkx2-5 and Isl1, suggesting that they share a developmental origin with multipotent Nkx2 5+/Isl1+ progenitors. 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 heart3,4. 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.