Mapping the senescent stromal landscape and altered the immune microenvironment in PCOS endometrium

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting approximately 10% of reproductive-aged women and is a major cause of infertility. Inadequate endometrial receptivity is a pivotal contributor to this infertility, but its underlying cellular mechanisms remain poorly understood. In this study, we employed single-cell RNA sequencing to map the transcriptional landscape of human endometrial tissues from PCOS patients and controls. Our analysis revealed notable alterations in cellular composition and communication. Stromal cells, the most abundant endometrial population, exhibited significant cell cycle dysregulation and reduced proliferative capacity. While certain immune clusters showed increased proliferative activity, we further confirmed accelerated cellular senescence in both stromal and epithelial compartments, suggesting a basis for impaired endometrial regeneration. Additionally, we uncovered substantial remodeling of the immune microenvironment, characterized by a marked reduction in T cells and an expansion of natural killer cells. Integrated ligand-receptor interaction analysis identified dysregulation of critical signaling pathways, including WNT, HGF, FGF, and FAS. Collectively, our findings provide a high-resolution cellular atlas of PCOS endometrium. They highlight stromal senescence and immune dysregulation as novel, interlinked pathways associated with endometrial dysfunction and impaired receptivity. These insights offer new therapeutic avenues for improving endometrial function and pregnancy outcomes in women with PCOS.