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

Summary: 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. : 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. Keywords: prostaglandin E2, cyclooxygenase-1, BMP4, mesoderm, differentiation, human embryonic stem cells, β-cateni