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Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart

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 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.

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Figure 1: Cardiac Wt1 and Wt1-driven GFPCre expression.
Figure 2: Wt1 -derived cells differentiate into cardiomyocytes.
Figure 3: Wt1 -expressing epicardial cells differentiate into cardiomyocytes.
Figure 4: Proepicardium arises from Nkx2-5 + precursors.

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Acknowledgements

This work was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health, USA, the American Heart Association, and by a charitable donation from E. P. Marram and K. K. Carpenter. We thank the Schwartz, Harvey, Schneider, Yanagisawa, Evans, Soriano, Orkin and Nagy laboratories for contributing mouse strains used in this study.

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Correspondence to William T. Pu.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with Legends and Supplementary Table 1. (PDF 4602 kb)

Supplementary Movie 1

This file contains Supplementary Movie 1 showing spontaneous contraction in Wt1GFPCre/+; Z/Red cells. (MOV 554 kb)

Supplementary Movie 2

This file contains Supplementary Movie 2 showing calcium transients in a Wt1GFPCre/+; Z/Red cell, loaded with the calcium-sensitive indicator Fluo-4 AM. (MOV 1147 kb)

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Zhou, B., Ma, Q., Rajagopal, S. et al. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454, 109–113 (2008). https://doi.org/10.1038/nature07060

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