The postpartum uterus reveals compartment-specific remodeling processes with distinct immune signatures

Introduction The endometrium exhibits the ability to regenerate without scarring after menstruation or parturition. Postpartum uterine repair occurs in a unique environment, shaped by peripartum immune responses. However, the mechanisms leading to healing or excessive fibrosis remain poorly understood. This study aimed to evaluate the drastic postpartum changes and the involvement of the immune milieu in the process of full wound regeneration. Methods Publicly available scRNA-seq data of human myometrium from non-pregnant or postpartum day 7 individuals were analyzed. Allogenically mated and virgin C57/BL6 female mice served as models for human postpartum healing. Uterine tissues were analyzed by flow cytometry, immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction. Results Human myometrial scRNA-seq revealed a sustained upregulation of immune responses in a context of degrowth of muscle components by postpartum day 7. As shown in mice, the size of the myometrium rapidly retracts. Particularly, the gradual resorption of the main site of leukocyte infiltration during pregnancy and postpartum, the mesometrial triangle, grants restoration of myometrial layers, dispersed during pregnancy to accommodate the leucocyte aggregates and growing conceptus. This region, encircling the lesions left by placental detachment, abundantly recruits macrophages that remain CD206 neg . This inflammatory reaction coincides with elevated levels of Tnf , Il2 , and Ifng , neovascularization, and cell death, and is balanced by increased Il10 levels. CD8 + T cells also seeded the mesometrial triangle, along with myofibroblasts surrounding the placental detachment clot until healing. This immune response was confined to the mesometrial area by a collagen-rich capsule. In turn, neighboring myometrial macrophages, largely expressing CD206, expanded during early remodeling to retract at homeostasis. Conclusion In healthy postpartum uterus tissue, we identified the myometrium, endometrium, and mesometrial triangle as distinct anatomical compartments undergoing remodeling, each with unique yet interconnected processes. Within these, the distribution of F4/80 + CD206 + and F4/80 + CD206 neg macrophage populations corresponded to different levels of tissue disruption. Inflammation, highly restricted by a collagen capsule and enhanced IL10, resolved to endorse myometrium integrity. Whether these mechanisms safeguard the myometrium from excessive immune responses, often linked to fibrosis, requires further empirical investigation.