Endothelial cells regulate cardiomyocyte development from embryonic stem cells.
The molecules and environment that direct pluripotent stem cell differentiation into cardiomyocytes are largely unknown. Here, we determined a critical role of receptor tyrosine kinase, EphB4, in regulating cardiomyocyte generation from embryonic stem (ES) cells through endothelial cells. The number of spontaneous contracting cardiomyocytes, and the expression of cardiac-specific genes, including alpha-MHC and MLC-2V, was significantly decreased in EphB4-null ES cells. EphB4 was expressed in endothelial cells underneath contracting cardiomyocytes, but not in cardiomyocytes. Angiogenic inhibitors, including endostatin and angiostatin, inhibited endothelial cell differentiation and diminished cardiomyogenesis in ES cells. Generation of functional cardiomyocytes and the expression of cardiac-specific genes were significantly enhanced by co-culture of ES cells with human endothelial cells. Furthermore, the defects of cardiomyocyte differentiation in EphB4-deficient ES cells were rescued by human endothelial cells. For the first time, our study demonstrated that endothelial cells play an essential role in facilitating cardiomyocyte differentiation from pluripotent stem cells. EphB4 signaling is a critical component of the endothelial niche to regulate regeneration of cardiomyocytes.
Chen
Kang
K
Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Bai
Hao
H
Arzigian
Melanie
M
Gao
Yong-Xing
YX
Bao
Jing
J
Wu
Wen-Shu
WS
Shen
Wei-Feng
WF
Wu
Liqun
L
Wang
Zack Z
ZZ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D036388:Ephrin-B2; D036224:Receptor, EphB4