A regulatory pathway involving Notch1/β-catenin/Isl1 determines cardiac progenitor cell fate.

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Abstract
Notch1 inhibits cardiac progenitor cell expansion by preventing the accumulation of phosphorylated β-catenin, which normally promotes their proliferation. In a feedback loop, Notch1 positively regulates the expression of cardiac transcription factors to induce progenitor cell differentiation, whereas β-catenin has the reverse effect. Regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/β-catenin signalling, which promotes expansion of CPCs1,2,3, is negatively regulated by Notch1-mediated control of phosphorylated β-catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and β-catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs before their differentiation4, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involves unanticipated functions of β-catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.