Single-cell sequencing uncovers disrupted stromal-macrophage communication as a driver of intrauterine adhesion progression

Intrauterine adhesions (IUA), characterized by endometrial fibrosis, pose a serious threat to women's reproductive health, yet their molecular mechanisms remain poorly understood. Here, we use single-cell RNA sequencing (scRNA-seq) to profile 139,395 single cells from nine individuals in the proliferative phase. We identify seven stromal and five macrophage subsets, revealing increased immune cell infiltration and a profibrotic shift in macrophage states. Immunohistochemistry confirms elevated CD68⁺ macrophages and higher expression of S100A8, CCL2, CCL5, and SPP1 in IUA tissues. In vitro, macrophage-derived CCL5 and SPP1 promote fibroblast-to-myofibroblast transition. Trajectory and ligand-receptor analysis highlight profibrotic macrophage lineages and TGF-β signaling as a key driver of fibrosis. Integration with secretory-phase single-cell data provides a comprehensive view of IUA across menstrual phases. These findings uncover a pivotal role for macrophage-stromal interactions in IUA progression and suggest potential therapeutic targets.