Kwon Chulan, Qian Li, Cheng Paul, Nigam Vishal, Arnold Joshua, Srivastava Deepak
Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
Nat Cell Biol. 2009 Aug;11(8):951-7. doi: 10.1038/ncb1906. Epub 2009 Jul 20.
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/beta-catenin signalling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated beta-catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and beta-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 beta-catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.
多能心脏祖细胞（CPC）的扩增以及随后分化为心肌细胞、平滑肌细胞或内皮细胞的调控，是基础心血管生物学和心脏再生医学的一个基本方面。然而，支配这些决定的机制仍不清楚。在此，我们表明，促进CPC扩增的Wnt/β-连环蛋白信号通路，受到Notch1介导的对CPC内磷酸化β-连环蛋白积累的控制的负调控，并且CPC中的Notch1活性是其分化所必需的。Notch1正向调控，而β-连环蛋白负向调控心脏转录因子Isl1、Myocd和Smyd1的表达。令人惊讶的是，通常在CPC分化前短暂表达的Isl1的破坏，导致体内和胚胎干细胞（ES）系统中CPC的扩增。此外，Isl1是CPC分化为心肌细胞和平滑肌细胞所必需的，但不是内皮细胞。这些发现揭示了一个控制CPC扩增和细胞命运的调控网络，该网络涉及β-连环蛋白、Notch1和Isl1的意外功能，这些功能可能被用于涉及CPC的再生方法。
