Uterine Natural Killer Cell-Mediated Clearance of Senescent Cells: A Novel Mechanism in Endometrial Decidualization and Implications for Endometriosis-Associated Infertility

Project Summary Endometriosis affects approximately 10% of reproductive-age women and is a major contributor to infertility, pregnancy loss, and chronic pelvic pain worldwide. This project aims to elucidate the role of uterine natural killer (uNK) cells in regulating endometrial clearance of senescent cells and immune balance, a process disrupted in endometriosis-associated reproductive failure5. Therefore, it is essential to establish physiologically relevant models to study the influence of the immune microenvironment on fertility and regeneration. Specific Aim 1 will develop and characterize a novel 3D endometrial immune microsystem incorporating menstrual effluent patient-derived uNK, stromal, and epithelial cells to investigate how chronic inflammation alters uNK function and senescent cell crosstalk ex vivo. Specific Aim 2 will use a genetically engineered Nkp46-GFP reporter mouse to spatiotemporally map uNK subset dynamics and their interactions with senescent cells during continuous decidual remodeling throughout early pregnancy. This integrative approach combining advanced imaging, flow cytometry, and transcriptomics will provide unprecedented insight into immune regulation of endometrial health and disease. Findings have the potential to reveal novel therapeutic targets to improve fertility outcomes and reduce pregnancy complications in women with endometriosis.