Prostaglandin E(2) Is Required for BMP4-Induced Mesoderm Differentiation of Human Embryonic Stem Cells.
Prostaglandin E(2) Is Required for BMP4-Induced Mesoderm Differentiation of Human Embryonic Stem Cells.
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BMP4 诱导人胚胎干细胞中胚层分化需要前列腺素 E2
DOI：
10.1016/j.stemcr.2018.01.024
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发表时间：
2018-03-13
影响因子：
5.9
通讯作者：
Pei X
中科院分区：
文献类型：
--
作者：
Zhang B;He L;Liu Y;Zhang J;Zeng Q;Wang S;Fan Z;Fang F;Chen L;Lv Y;Xi J;Yue W;Li Y;Pei X
在人类胚胎干细胞（hESCs）分化过程中，准确控制早期细胞命运是获得纯治疗性细胞群的关键。骨形态发生蛋白4 （Bone morphogenetic protein 4, BMP4）是ESCs中重要的中胚层诱导剂。然而，BMP4诱导中胚层细胞命运决定的分子机制尚不清楚。在这里，我们证明了生物活性脂质前列腺素E2 （PGE2）对BMP4诱导hESCs中胚层规格的要求。我们发现BMP4直接调控PGE2合成的关键酶COX-1的表达，并促进PGE2的生成。更重要的是，在缺乏BMP4的情况下，强制COX-1表达或PGE2处理足以通过激活EP2-PKA信号和调节β-catenin的核易位来启动hESCs的中胚层特异性。总之，我们的研究结果为BMP调控PGE2合成及其下游信号传导在hESCs中启动中胚层承诺的关键作用提供了见解。COX-1和PGE2在hESCs的中胚层分化中起关键作用，特异性抑制COX-1抑制hESCs的中胚层分化BMP4直接上调COX-1的转录，PGE2主要通过EP2-PKA-GSK3β/β-catenin信号通路刺激分化。Pei和同事证明了BMP4诱导hESCs中胚层分化需要前列腺素E2。这项工作揭示了hESCs早期细胞命运决定的机制，并通过增加或阻断PGE2信号通路，为中胚层诱导或神经外胚层分化策略提供了见解。
The accurate control of early cell fate specification during differentiation of human embryonic stem cells (hESCs) is critical for acquiring pure therapeutic cell populations of interest. Bone morphogenetic protein 4 (BMP4) is a key mesoderm inducer from ESCs. However, the molecular mechanism of the mesodermal cell fate decision induced by BMP4 remains unclear. Here, we demonstrate the requirement of a bioactive lipid, prostaglandin E2 (PGE2), for the mesoderm specification from hESCs by BMP4 induction. We show that BMP4 directly regulates the expression of the key enzyme for PGE2 synthesis, COX-1, and promotes PGE2 production. More importantly, in the absence of BMP4, forced COX-1 expression or PGE2 treatment is sufficient to initiate mesoderm specification of hESCs by activation of EP2-PKA signaling and modulation of nuclear translocation of β-catenin. Together, our findings provide insights into the critical role of BMP regulation of PGE2 synthesis and its downstream signaling in initiating mesoderm commitment of hESCs. COX-1 and PGE2 played pivotal roles in the mesoderm specification of hESCs Specific inhibition of COX-1 suppressed mesoderm differentiation of hESCs BMP4 directly upregulated the transcription of the COX-1 PGE2 stimulated differentiation mainly via the EP2-PKA-GSK3β/β-catenin signaling pathway In this article, Pei and colleagues demonstrate the requirement of prostaglandin E2 for the mesoderm specification from hESCs by BMP4 induction. This work reveals a mechanism for the early cell fate determination of hESCs and provides insights into strategies for mesoderm induction or neuroectoderm specification through increasing or blocking the PGE2 signal pathway.
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DOI：
10.1073/pnas.112217799
发表时间：
2002-06-11
影响因子：
11.1
作者：
Grosser, T;Yusuff, S;FitzGerald, GA
通讯作者：
FitzGerald, GA
影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
DOI：
10.1073/pnas.220413597
发表时间：
2000-10-24
影响因子：
11.1
作者：
Fang, XJ;Yu, SX;Mills, GB
通讯作者：
Mills, GB
影响因子：
4.8
作者：
Fujino, H;West, KA;Regan, JW
通讯作者：
Regan, JW
DOI：
10.1073/pnas.112202999
发表时间：
2002-05-28
影响因子：
11.1
作者：
Rocca, B;Secchiero, P;Patrono, C
通讯作者：
Patrono, C