MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal
MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal
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DOI：
10.1111/j.1432-0436.2006.00143.x
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发表时间：
2007-04-01
期刊：
影响因子：
2.9
通讯作者：
Deng, Hongkui
中科院分区：
文献类型：
--
作者：
Li, Jian;Wang, Guangwen;Deng, Hongkui
MEK/ERK信号在包括细胞增殖、分化和存活在内的一系列细胞功能中起着至关重要的作用，最近有报道通过拮抗STAT3活性来负向调节小鼠胚胎干细胞(MESC)的自我更新。然而，它在人类胚胎干细胞(HESCs)中的作用仍不清楚。在此，我们研究了MEK/ERK在控制hESC活性中的作用。我们证明MEK/ERK是hESCs中成纤维细胞生长因子途径的靶点。令人惊讶的是，我们发现，与mESCs相反，维持hESCs处于未分化状态需要高基础MEK/ERK活性。用特定的MEK抑制剂PD98059和U0126或RNA干扰抑制MEK/ERK活性，迅速导致自我更新能力的丧失。我们还发现MEK/ERK信号与PI3K/AKT信号在维持hESC多能性方面存在协同作用。然而，与PI3K/AKT信号通路相比，MEK/ERK信号通路在调节hESC的增殖和存活方面几乎或根本没有作用。加在一起..这些发现揭示了MEK/ERK信号在决定hESC细胞命运中的独特而关键的作用，并加深了我们对成纤维细胞生长因子途径维持hESC多能性背后的分子机制的理解。重要的是，这些数据清楚地表明了hESCs和mESCs在自我更新控制方面的显著差异。
MEK/ERK signaling plays a crucial role in a diverse set of cellular functions including cell proliferation, differentiation and survival, and recently has been reported to negatively regulate mouse embryonic stem cell (mESC) self-renewal by antagonizing STAT3 activity. However, its role in human ESCs (hESCs) remains unclear. Here we investigated the functions of MEK/ERK in controlling hESC activity. We demonstrated that MEK/ERK kinases were targets of fibroblast growth factor (FGF) pathway in hESCs. Surprisingly, we found that, in contrast to mESCs, high basal MEK/ERK activity was required for maintaining hESCs in an undifferentiated state. Inhibition of MEK/ERK activity by specific MEK inhibitors PD98059 and U0126, or by RNA interference, rapidly caused the loss of self-renewal capacity. We also showed that MEK/ERK signaling cooperated with phosphoinositide 3-kinase (PI3K)/AKT signaling in maintaining hESC pluripotency. However, MEK/ERK signaling had little or no effect on regulating hESC proliferation and survival, in contrast to PI3K/AKT signaling. Taken together.. these findings reveal the unique and crucial role of MEK/ERK signaling in the determination of hESC cell fate and expand our understanding of the molecular mechanisms behind the FGF pathway maintenance of hESC pluripotency. Importantly, these data make evident the striking differences in the control of self-renewal between hESCs and mESCs.