Inhibition of ERK1/2 prevents neural and mesendodermal differentiation and promotes human embryonic stem cell self-renewal
Inhibition of ERK1/2 prevents neural and mesendodermal differentiation and promotes human embryonic stem cell self-renewal
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DOI：
10.1016/j.scr.2010.06.002
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发表时间：
2010-09-01
影响因子：
1.2
通讯作者：
Andrews, Peter W.
中科院分区：
文献类型：
--
作者：
Na, Jie;Furue, Miho K.;Andrews, Peter W.
细胞外信号调节激酶（ERK）在胚胎发育过程中具有重要的功能。然而，它们在胚胎干细胞（ES）中的作用是有争议的。先前的研究报道，与小鼠ES细胞相反，如果ERK 1/2被抑制，则人ES细胞分化。我们使用化学定义的培养系统重新检查了ERK 1/2在人ES细胞中的作用，发现当ERK 1/2被特定的化学抑制剂阻断时，神经和中内胚层分化被阻止，但细胞对BMP诱导的分化变得敏感。ERK 1/2的抑制通过阻止细胞粘附和存活显著降低了人ES细胞的克隆形成性。当避免这种负面影响时，我们能够在含有FGF 2和激活素A但不含BMP 4的化学成分确定的培养系统中，在存在ERK 1/2抑制剂的情况下维持人ES细胞自我更新超过3个月。我们的研究结果表明，FGF/ERK 1/2信号在人ES细胞的功能结果的影响，激活素A/TGF β和BMP活性的相对水平。此外，人ES细胞中ERK 1/2的激活是适当的神经和中内胚层分化所必需的。与小鼠ES细胞相反，当ERK 1/2被抑制时，低水平的BMP 4足以启动胚外分化。(C)2010爱思唯尔有限公司版权所有。
Extracellular signal-regulated kinases (ERKs) have many important functions during embryogenesis. However, their role in embryonic stem (ES) cells is controversial. Previous studies reported that, in contrast to mouse ES cells, human ES cells differentiate if ERK1/2 is inhibited. We reexamined the role of ERK1/2 in human ES cells using a chemically defined culture system and found that when ERK1/2 is blocked with specific chemical inhibitors, neural and mesendodermal differentiation is prevented, but cells become sensitive to BMP-induced differentiation. Inhibition of ERK1/2 significantly reduced the clonogenicity of human ES cells by preventing cell adhesion and survival. When this negative effect was avoided, we were able to maintain human ES cell self-renewal for more than 3 months in the presence of ERK1/2 inhibitors in a chemically defined culture system containing FGF2 and activin A but no BMP4. Our results suggest that the functional outcome of FGF/ERK1/2 signaling in human ES cells is influenced by the relative levels of activin A/TGF beta and BMP activity. Moreover, activation of ERK1/2 in human ES cells is required for proper neural and mesendodermal differentiation. In contrast to mouse ES cells, a low level of BMP4 is sufficient to initiate extraembryonic differentiation when ERK1/2 is inhibited. (C) 2010 Elsevier B.V. All rights reserved.