Prostaglandin E2 and MPA-Mediated Human Endometrial Stromal Cell Decidualization

Development of the decidua, the transient maternal tissue contacting the fetus during gestation, is the hallmark of reproduction in many placental mammals. Differentiation of decidual stromal cells is known to be induced by stimuli that activate progesterone receptor and the cyclic AMP/protein kinase A (cAMP/PKA) pathway. The physiological upstream stimulus of PKA has not been confidently identified, although several candidates have been proposed. To bypass this uncertainty in vitro, treatment with membrane-permeable cyclic AMP and progestin has prevailed. Phylogenetic inference suggests that prostaglandin E2 (PGE2) was the stimulus that ancestrally induced decidualization. Accordingly, we decidualized human endometrial fibroblasts using PGE2 and progestin. Transcriptomic comparison to a cAMP-based protocol revealed shared activation of core decidual cell genes between both treatments, and increased induction of senescence-associated genes under cAMP treatment. Single-cell transcriptomics of PGE2-mediated decidualization revealed a distinct early activated state transitioning to a differentiated decidual state, but did not identify a unique developmental trajectory towards the senescent decidual state reported in recent literature. Investigation of the signal transduction underlying PGE2-mediated decidualization showed that it depends upon progestin-dependent induction of PGE2 receptor 2 (PTGER2) and PKA, the kinase activated by PTGER2.