Volume 21, No 4, Apr 2011

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 21 Issue 4, April 2011: 579-587

ORIGINAL ARTICLES

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

Qiangzhe Zhang^1,*, Junjie Jiang^1,*, Pengcheng Han^1,*, Qi Yuan¹, Jing Zhang¹, Xiaoqian Zhang¹, Yanyan Xu¹, Henghua Cao¹, Qingzhang Meng¹, Li Chen¹, Tian Tian¹, Xin Wang², Pu Li¹, Jurgen Hescheler³, Guangju Ji¹ and Yue Ma¹

¹National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Rd., Chaoyang District, Beijing 100101, China

²Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, 320 Yueyang Rd., Shanghai 200032, China

³Center for Physiology and Pathophysiology, Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany Correspondence: Yue Maa, Guangju Jib,(yuema@ibp.ac.cn; gj28@ibp.ac.cn)

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 pan-retinoic 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 cultures. 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 differentiation efficiency, 83% of the cardiomyocytes in Noggin+RAi-treated cultures had embryonic ventricular-like 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 Ca²⁺ 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 signals.

Cell Research (2011) 21:579-587. doi:10.1038/cr.2010.163; published online 23 November 2010

FULL TEXT | PDF

Browse 1889