视黄酸通路的启示——从心脏发育到心肌谱系定向分化

多潜能干细胞具有无限增殖的能力,并能够分化为心肌细胞,因此在心脏再生方面拥有巨大潜力.胚胎发育过程为干细胞定向分化提供了重要线索,在过去的几年中,通过操控心脏发育关键通路,在心肌定向分化方面取得了重要进展,但是现有的分化方法仍不能稳定地诱导心肌细胞,表明现有的通路不能有效解决这些问题.视黄酸(RA)通路在心脏发育过程中发挥重要作用,RA缺失会导致心房变小、心室小梁减少、心肌壁增厚且细胞间连接松散.在体外心肌定向分化过程中,RA多用于促进多潜能干细胞向心房分化.但从RA通路基因敲除小鼠的表型来看,除了调控心肌亚型分化,RA在多个发育阶段发挥重要作用.深入解析RA在心肌分化各阶段的作用机制,将有助于获得高质量的心肌细胞.同时,研究RA在心内膜和心外膜分化中的作用机制也有助于解释RA通路敲除小鼠的心脏异常.总之,从RA在胚胎发育中的作用来看,需要更多的体外研究来揭示RA在心肌谱系分化中的作用.本文综述了RA通路在心脏发育的心肌分化过程中的作用,并探讨了需要解决的问题.

Functions of Retinoic Acid in Heart Development and Cardiac Lineage Differentiation

Pluripotent stem cells (PSCs) hold unlimited proliferation ability and the potential to generate cardiomyocytes, providing new sources of cells for heart regeneration. Development biology provides important clues for directed differentiation. During the past few years, great progresses on cardiomyocyte differentiation have been made by manipulating cardiac developmental pathways. However, the protocol for directed cardiomyocyte differentiation is not reproductive between cell lines, indicating that current pathways are not efficient enough. Retinoic acid (RA) pathway deficiency in embryo results in severe heart development abnormalities, including impaired atria development, reduced trabeculae, thickened myocardium and loosely attached cells in ventricle. During directed cardiomyocyte differentiation, RA were mainly used for atrial cardiomyocytes induction from pluripotent stem cells. However, based on the phenotypes of RA pathway knockout mice, the function of RA is not limited to cardiac subtypes specification. Exploring the mechanisms of RA on different stages of cardiac differentiation will contribute to directed differentiation of cardiomyocyte. Meanwhile, clarifying the mechanisms of RA in endocardial and epicardial differentiation will explain the impaired heart development of RA deficiency. In conclusion, according to the functions of RA in heart development, more in vitro studies on cardiac lineages differentiation should be performed to uncover the mechanisms of RA. Here, we reviewed the functions of RA in cardiac development and cardiomyocyte differentiation, and discussed the issues need to be solved further.