Yes‐associated protein mediates human embryonic stem cell‐derived cardiomyocyte proliferation: Involvement of epidermal growth factor receptor signaling

• Published in: Journal of cellular physiology 2018-10, Vol.233 (10), p.7016-7025
• Main Authors: Park, Somi, Choe, Museog, Yeo, Hancheol, Han, Hojae, Kim, Joongsun, Chang, Woocheol, Yun, Seungpil, Lee, Hojin, Lee, Minyoung
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Cardiomyocytes; Cell culture; Cell Differentiation - physiology; Cell proliferation; Cell Proliferation - physiology; Density; Epidermal growth factor; Epidermal Growth Factor - metabolism; epidermal growth factor receptor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Extracellular signal-regulated kinase; Human Embryonic Stem Cells - cytology; human embryonic stem cell‐derived cardiomyocytes; Humans; Kinases; lowdensity culture; Myocytes, Cardiac - metabolism; Phosphoproteins - metabolism; Phosphorylation; Pluripotency; Pluripotent Stem Cells - cytology; proliferation; Proteins; Signal Transduction - physiology; Stem cells; Transcription Factors; Yes-associated protein
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26625

Unlike mature cardiomyocytes, human pluripotent stem cell‐derived cardiomyocytes exhibit higher proliferative capacity; however, the underlying mechanisms involved are yet to be elucidated. Here, we revealed that the Yes‐associated protein (YAP) plays a critical role in regulating cell proliferation in association with epidermal growth factor receptor (EGFR) in human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs). Our results show that low‐density culture significantly promotes the proliferation of hESC‐CMs via YAP. Interestingly, the low‐density culture‐induced YAP expression further induced EGFR expression, without any alterations in the activity of EGFR and its two major downstream kinases, ERK, and AKT. However, treatment of a low‐density‐culture of hESC‐CMs with epidermal growth factor (EGF) increased proliferation via phosphorylation of EGFR, ERK, and AKT, and the EGF‐induced phosphorylation of EGFR, ERK, and AKT was significantly higher in low‐density hESC‐CMs than in high‐density hESC‐CMs. Furthermore, the EGF‐induced activation of EGFR, ERK, and AKT increased YAP expression and subsequently proliferation. In conclusion, YAP mediates both low‐density culture‐induced and EGF‐induced proliferation of hESC‐CMs in low‐density culture conditions. (i) Low‐density culture promotes proliferation of hESC‐derived cardiomyocytes via YAP. (ii) EGF receptor expression is enhanced by low density culture in hESC‐derived cardiomyocytes. (iiI) YAP mediates EGF‐induced proliferation of hESC‐derived cardiomyocytes.