College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
J Cell Physiol. 2018 Oct;233(10):7016-7025. doi: 10.1002/jcp.26625. Epub 2018 Apr 25.
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.
与成熟的心肌细胞不同，人类多能干细胞衍生的心肌细胞表现出更高的增殖能力；然而，其中涉及的潜在机制仍有待阐明。在这里，我们揭示了 Yes 相关蛋白（YAP）在与表皮生长因子受体（EGFR）相关联的情况下，在人类胚胎干细胞衍生的心肌细胞（hESC-CMs）中对于调节细胞增殖起着关键作用。我们的结果表明，低密度培养通过 YAP 显著促进 hESC-CMs 的增殖。有趣的是，低密度培养诱导的 YAP 表达进一步诱导 EGFR 表达，而 EGFR 的活性及其两个主要下游激酶 ERK 和 AKT 没有任何变化。然而，用表皮生长因子（EGF）处理 hESC-CMs 的低密度培养通过 EGFR、ERK 和 AKT 的磷酸化增加增殖，并且在低密度 hESC-CMs 中 EGF 诱导的 EGFR、ERK 和 AKT 的磷酸化明显高于高密度 hESC-CMs。此外，EGF 诱导的 EGFR、ERK 和 AKT 的激活增加了 YAP 的表达，随后促进了增殖。总之，YAP 在低密度培养条件下介导了 hESC-CMs 的低密度培养诱导的和 EGF 诱导的增殖。
