Singh Amar M, Li Feng-Qian, Hamazaki Takashi, Kasahara Hideko, Takemaru Ken-ichi, Terada Naohiro
Department of Pathology, University of Florida College of Medicine, Box 100275, Gainesville, FL 32610, USA.
Circulation. 2007 Feb 6;115(5):617-26. doi: 10.1161/CIRCULATIONAHA.106.642298. Epub 2007 Jan 29.
Embryonic stem cell (ESC)-derived cardiomyocytes are anticipated to serve as a useful source for future cell-based cardiovascular disease therapies. Research emphasis is currently focused on determining methods to direct the differentiation of ESCs to a large population of cardiomyocytes with high purity. To this aim, understanding the molecular mechanisms that control ESC-to-cardiomyocyte differentiation should play a critical role in the development of this methodology. The Wnt/beta-catenin signaling pathway has been implicated in both embryonic cardiac development and in vitro ESC differentiation into cardiomyocytes. Chibby is a recently identified nuclear protein that directly binds to beta-catenin and antagonizes its transcriptional activity.
Chibby was ubiquitously expressed in early stages of ESC differentiation but upregulated during cardiomyocyte specification. Of interest, the Chibby gene promoter has multiple binding sites for the cardiac-specific homeodomain protein Nkx2.5, and its promoter activity was indeed positively regulated by Nkx2.5. Furthermore, overexpression of Chibby increased cardiac differentiation of ESCs, whereas loss of Chibby by RNAi impaired cardiomyocyte differentiation.
These data illustrate the regulation and function of Chibby in facilitating cardiomyocyte differentiation from ESCs. By revealing molecular mechanisms that control ESC-to-cardiomyocyte differentiation, this study will allow for the future development of technologies to improve cardiomyocyte differentiation from ESCs.
胚胎干细胞(ESC)来源的心肌细胞有望成为未来基于细胞的心血管疾病治疗的有用来源。目前研究重点集中在确定将胚胎干细胞定向分化为大量高纯度心肌细胞的方法。为实现这一目标,了解控制胚胎干细胞向心肌细胞分化的分子机制对于该方法的开发应起到关键作用。Wnt/β-连环蛋白信号通路已被证明与胚胎心脏发育以及体外胚胎干细胞分化为心肌细胞有关。Chibby是最近发现的一种核蛋白,它直接与β-连环蛋白结合并拮抗其转录活性。
Chibby在胚胎干细胞分化的早期阶段广泛表达,但在心肌细胞特化过程中上调。有趣的是,Chibby基因启动子有多个心脏特异性同源结构域蛋白Nkx2.5的结合位点,其启动子活性确实受到Nkx2.5的正向调控。此外,Chibby的过表达增加了胚胎干细胞的心脏分化,而通过RNA干扰使Chibby缺失则损害了心肌细胞的分化。
这些数据阐明了Chibby在促进胚胎干细胞向心肌细胞分化中的调控作用和功能。通过揭示控制胚胎干细胞向心肌细胞分化的分子机制,本研究将为未来改进胚胎干细胞向心肌细胞分化的技术发展提供可能。