Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals  

作　　者：Qiangzhe Zhang Junjie Jiang Pengcheng Han Qi Yuan Jing Zhang Xiaoqian Zhang Yanyan Xu Henghua Cao Qingzhang Meng Li Chen Tian Tian Xin Wang Pu Li Jurgen Hescheler Guangju Ji Yue Ma 

机构地区：[1]National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Rd., Chaoyang District, Beijing 100101, China [2]Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, 320 Yueyang Rd., Shanghai 200032, China [3]Center for Physiology and Pathophysiology, Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany

出　　处：《Cell Research》2011年第4期579-587,共9页细胞研究（英文版）

摘　　要：Although myocyte cell transplantation studies have suggested a promising therapeutic potential for myocardial infarction, a major obstacle to the development of clinical therapies for myocardial repair is the difficulties associated with obtaining relatively homogeneous ventricular myocytes for transplantation. Human embryonic stem cells （hESCs） are a promising source of cardiomyocytes. Here we report that retinoid signaling regulates the fate specification of atrial versus ventricular myocytes during cardiac differentiation of hESCs. We found that both Noggin and the panretinoic acid receptor antagonist BMS-189453 （RAi） significantly increased the cardiac differentiation efficiency of hESCs. To investigate retinoid functions, we compared Noggin＋RAi-treated cultures with Noggin＋RA-treated cul- tures. Our results showed that the expression levels of the ventricular-specific gene IRX-4 were radically elevated in Noggin＋RAi-treated cultures. MLC-2V, another ventricular-specific marker, was expressed in the majority of the cardiomyocytes in Noggin＋RAi-treated cultures, but not in the cardiomyocytes of Noggin＋RA-treated cultures. Flow cytometry analysis and electrophysiological studies indicated that with 64.7 ±0.88% （mean ± s.e.m） cardiac differen- tiation efficiency, 83% of the cardiomyocytes in Noggin＋RAi-treated cultures had embryonic ventricular-llke action potentials （APs）. With 50.7 ± 1.76% cardiac differentiation efficiency, 94% of the cardiomyocytes in Noggin＋RA- treated cultures had embryonic atrial-like APs. These results were further confirmed by imaging studies that assessed the patterns and properties of the Ca^2＋ sparks of the cardiomyocytes from the two cultures. These findings demonstrate that retinoid signaling specifies the atrial versus ventricular differentiation of hESCs. This study also shows that relatively homogeneous embryonic atrial- and ventricular-like myocyte populations can be efficiently derived from hESCs by specifically regulating Noggin and retinoid

关 键 词：human embryonic stem cell cardiac subtype specification heart development 

分 类 号：Q813[生物学—生物工程] Q463