Single-Cell and Spatial Multi-Omics Unravel Estrogen-Driven Remodeling of the Prolapsed Uuterine Microenvironment via Fibroblast Reprogramming and Intercellular Communication

The clinical paradox of local estrogen therapy in pelvic organ prolapse—its widespread application juxtaposed with inconsistent therapeutic outcomes—highlights a critical gap in our understanding of its actions within the native tissue architecture. To resolve this, we employed high-definition spatial transcriptomics, achieving a near-cellular resolution map of the postmenopausal vaginal wall. This spatial atlas directly visualized estrogen’s core mechanism: the orchestration of a structured HAS1 + fibroblast-pericyte reparative niche around vasculature. Estrogen directs the recruitment of POLR3G-driven, HAS1 + fibroblasts into this precise micro-anatomical location, enabling their functional coupling with pericytes. This co-localization facilitates a rewired fibroblast-pericyte signaling axis, enhancing pro-repair communication. Computational pharmacology further affirms this niche as a druggable functional unit. Our findings establish a new paradigm: estrogen's efficacy is not mediated by broad tissue stimulation, but through the precise spatial engineering of a multicellular repair unit, a mechanism unveiled only through high-definition spatial mapping and one that redefines the future of targeted therapeutic strategies.