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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 E 2 (PGE 2 ), for the mesoderm specification from hESCs by BMP4 induction. We show that BMP4 directly regulates the expression of the key enzyme for PGE 2 synthesis, COX-1, and promotes PGE 2 production. More importantly, in the absence of BMP4, forced COX-1 expression or PGE 2 reatment 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 PGE 2 synthesis and its downstream signaling in initiating mesoderm commitment of hESCs.

Prostaglandin E2 Is Required for BMP4-Induced Mesoderm Differentiation of Human Embryonic Stem Cells