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

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.