BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways
BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways
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DOI：
10.1073/pnas.0401367101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Zhao, GQ
中科院分区：
文献类型：
--
作者：
Qi, XX;Li, TG;Zhao, GQ
多能干细胞的命运在早期胚胎发育过程中受到严格控制。胚胎干细胞（ES细胞）的体外分化和维持依赖于饲养细胞来源的生长因子，这些生长因子在很大程度上是未知的。为了剖析管理多能性的机制，我们进行了筛选，以确定由小鼠胚胎成纤维细胞STO细胞产生的因子，并需要维持ES细胞的多能性。其中一个因素是骨形态发生蛋白4（BMP 4）。出乎意料的是，BMP 4对ES细胞自我更新的主要作用是通过抑制细胞外受体激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）途径来实现的，并且ERK和p38 MAPK的抑制剂模拟BMP 4对ES细胞的作用。重要的是，SB203580对p38 MAPK途径的抑制克服了从缺乏功能性Alk3（BMP IA型受体）的胚泡获得ES细胞的阻断。这些结果揭示了多能干细胞生物学中BMP信号传导的范例。
The fate of pluripotent stem cells is tightly controlled during early embryonic development. Both the derivation and the maintenance of embryonic stem cells (ES cells) in vitro depend on feeder cell-derived growth factors that are largely unidentified. To dissect the mechanisms governing pluripotency, we conducted a screen to identify factors that are produced by mouse embryonic fibroblast STO cells and are required to maintain the pluripotency of ES cells. One of the factors is bone morphogenetic protein 4 (BMP4). Unexpectedly, the major effect of BMP4 on the self-renewal of ES cells is accomplished by means of the inhibition of both extracellular receptor kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways, and inhibitors of ERK and p38 MAPKs mimic the effect of BMP4 on ES cells. Importantly, inhibition of the p38 MAPK pathway by SB203580 overcomes the block in deriving ES cells from blastocysts lacking a functional Alk3, the BMP type IA receptor. These results uncover a paradigm for BMP signaling in the biology of pluripotent stem cells.