Single-cell RNA sequencing reveals a pro-fibrotic epithelial subpopulation contributing to endometrial dysfunction in polycystic ovary syndrome.

BACKGROUND: Endometrial dysfunction in women with polycystic ovary syndrome (PCOS) significantly contributes to adverse pregnancy outcomes, including recurrent implantation failure and high miscarriage rates. However, the specific roles of individual cell types in this dysfunction, particularly in non-obese and obese PCOS patients, remain unclear. METHODS: This study utilized single-cell RNA sequencing to comprehensively examine cellular heterogeneity in the proliferative-phase endometrium of non-obese PCOS, obese PCOS, and healthy controls. RESULTS: Notably, we identified a distinct subpopulation of endometrial epithelial cells (EC) exhibiting a predisposition for epithelial-mesenchymal transition, characterized by elevated expression of decorin (DCN) and extracellular matrix 1 (ECM1) (DCNhighECM1high EC2). The proportion of these cells was significantly higher in PCOS patients, potentially disrupting normal epithelial function and reducing endometrial receptivity. Analysis of cell-cell communication revealed a notable decrease in anti-fibrotic bone morphogenetic protein (BMP) signaling in fibroblasts targeting DCNhighECM1high EC2, coupled with a marked increase in pro-fibrotic transforming growth factor beta (TGFβ) signaling in immune cells targeting DCNhighECM1high EC2. These changes were further enhanced in obese PCOS patients compared to non-obese PCOS patients. CONCLUSIONS: The imbalance between the BMP and TGFβ pathways likely drives the fibrotic transformation of endometrial epithelial cells in both non-obese and obese PCOS patients. Obese phenotype further exacerbates the fibrotic tendency, and compromises endometrial receptivity. Our findings highlight potential therapeutic targets for managing endometrial dysfunction in PCOS.