Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis

Abstract

Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings unveil a previously unidentified dysfunction in BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals.

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis

“…CUT&RUN was performed as per previously published protocol 55 . Briefly, endometrial stromal cells were overexpressed with GREB1 plasmid construct (Genecopoeia, catalogue number: EX-Y4970-M91) and then treated with MPA for 4 h. Overexpressed cells were collected by trypsin digestion and frozen viably in the freezing medium (90% FBS with 10% DMSO) until experiment day.…”