Dissecting the Impact of Endometriosis on Decidualization and Trophoblast-Endometrial Interactions.

Implantation is a critical process in human development, initiated when the blastocyst-stage embryo establishes contact with the maternal endometrium. This interaction is mediated by trophoblast cells from the trophectoderm, which regulate early invasion and maternal-fetal crosstalk. Disruptions in trophoblast- endometrium interactions can lead to implantation failure, pregnancy loss, and complications such as preeclampsia. Women with endometriosis, a systemic condition affecting millions in the U.S., face an increased risk of infertility and pregnancy complications. However, the molecular mechanisms underlying these issues remain poorly understood, highlighting the need for models that accurately replicate trophoblast-endometrium dynamics in both healthy and diseased states. Existing in vitro models lack critical architectural and functional features, limiting their translational relevance. To address this gap, I developed a novel patient-derived 3D EndoMetrial Assembloid (EMA) that mimics key aspects of endometrial architecture, including epithelial, stromal, and uterine endothelial cells; hormone responsiveness; basement membrane secretion; and apical-out polarity. This platform enables physiologically relevant studies of trophoblast-endometrium interactions. This proposal will investigate the role of miRNAs in decidualization within the context of endometriosis, and how the disease affects trophoblast development and invasion. I propose to integrate advanced 3D tissue engineering, high-resolution imaging, extracellular vesicle analysis, and transcriptomic/functional assays to explore how endometriosis-associated decidualization defects influence trophoblast behavior. This study will provide insights into the mechanisms driving implantation defects and pregnancy complications by addressing fundamental questions about trophoblast-endometrium interactions in the context of endometriosis. Ultimately, these findings will be critical for the possible prevention of adverse pregnancy outcomes, offering a unique opportunity to inform future diagnostic and therapeutic strategies for improving reproductive outcomes in endometriosis patients.