Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway
Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway
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DOI：
10.1016/j.yjmcc.2005.09.007
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发表时间：
2005-12-01
影响因子：
5
通讯作者：
Murry, CE
中科院分区：
文献类型：
--
作者：
McDevitt, TC;Laflamme, MA;Murry, CE
来自普通实验动物的心肌细胞在分离后迅速退出细胞周期，阻碍了基础细胞生物学和应用如心肌修复的研究。在这里，我们研究了来自人类和小鼠胚胎干（ES）细胞的心肌细胞的增殖。小鼠ES细胞衍生的心肌细胞几乎没有增殖，而人心肌细胞在无血清条件下高度增殖（15- 25%BrdU +/肌节肌动蛋白+）。细胞仅表现出小的血清剂量反应。并且随着细胞分化的增加，增殖逐渐减慢。细胞密度和不同的基质附着因子均不影响心肌细胞增殖。阻断磷脂酰肌醇3-激酶（PI 3-激酶）和Akt显着降低心肌细胞增殖，而MEK抑制没有影响。胰岛素样生长因子-1（IGF-1）受体的抗体阻断显著抑制心肌细胞增殖，而IGF-1或IGF-2的加入以剂量依赖性方式刺激心肌细胞增殖。因此，来源于人ES细胞的心肌细胞在体外广泛增殖，并且它们的增殖似乎主要通过PI 3-激酶/Akt信号传导途径介导，使用IGF-1受体作为一种上游激活剂。该系统应允许鉴定人心肌细胞增殖的调节途径，并可促进用于治疗目的的人ES细胞的心肌细胞的扩增。(c)2005爱思唯尔有限公司保留所有权利。
Cardiomyocytes from common experimental animals rapidly exit the cell cycle upon isolation, impeding studies of basic cell biology and applications such as myocardial repair. Here we examined proliferation of cardiomyocytes derived from human and mouse embryonic stem (ES) cells. While mouse ES cell-derived cardiomyocytes showed little proliferation, human cardiomyocytes were highly proliferative under serum-free conditions (15-25% BrdU+/sarcomeric actin+). The cells exhibited only a small serum dose-response. and proliferation gradually slowed with increasing differentiation of the cells. Neither cell density nor different matrix attachment factors affected cardiomyocyte proliferation. Blockade of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt significantly reduced cardiomyocyte proliferation, whereas MEK inhibition had no effect. Antibody blocking of the insulin-like growth factor-1 (IGF-1) receptor significantly inhibited cardiomyocyte proliferation, while addition of IGF-1 or IGF-2 stimulated cardiomyocyte proliferation in a dose-dependent manner. Thus, cardiomyocytes derived from human ES cells proliferate extensively in vitro, and their proliferation appears to be mediated primarily via the PI 3-kinase/Akt signaling pathway, using the IGF-1 receptor as one upstream activator. This system should permit identification of regulatory pathways for human cardiomyocyte proliferation and may facilitate expansion of cardiomyocytes from human ES cells for therapeutic purposes. (c) 2005 Elsevier Ltd. All rights reserved.