TY - JOUR
T1 - A regulatory pathway involving Notch1/β-catenin/Isl1 determines cardiac progenitor cell fate
AU - Kwon, Chulan
AU - Qian, Li
AU - Cheng, Paul
AU - Nigam, Vishal
AU - Arnold, Joshua
AU - Srivastava, Deepak
N1 - Funding Information:
assistance, B. Taylor for manuscript and figure preparation and Srivastava lab members for helpful discussions. C.K. was supported by a fellowship from the American Heart Association (AHA) and California Institute for Regenerative Medicine (CIRM); D.S. was an Established Investigator of the AHA and was supported by grants from NHLBI/NIH and CIRM. This work was also supported by NIH/NCRR grant (C06 RR018928) to the Gladstone Institutes.
PY - 2009
Y1 - 2009
N2 - 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 CPCs, 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 differentiation, 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.
AB - 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 CPCs, 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 differentiation, 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.
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U2 - 10.1038/ncb1906
DO - 10.1038/ncb1906
M3 - Article
C2 - 19620969
AN - SCOPUS:68249120547
SN - 1465-7392
VL - 11
SP - 951
EP - 957
JO - Nature cell biology
JF - Nature cell biology
IS - 8
ER -