Mesenchymal-epithelial transition serves to rapidly, yet transiently, restore the endometrial epithelium during postpartum murine uterine regeneration.

The uterus is a remarkable organ in its ability to undergo extensive tissue damage during menstruation and parturition, yet achieves efficient, scar-free repair. Coordinated regulation of this regenerative process is essential for uterine homeostasis and fertility; however, the underlying mechanisms remain incompletely understood. Here, we demonstrate that mesenchymal-epithelial transition (MET) contributed to postpartum endometrial re-epithelialization using Significance: The mammalian endometrium undergoes repeated injury and repair during menstruation (women) and pregnancy (most eutherians), yet exhibits a remarkable capacity for rapid, scar-free healing that mediates infection, inflammation and hemorrhage. Despite its clinical relevance, the molecular regulation of endometrial regeneration remains poorly defined. Using a transgenic lineage-tracing mouse model, we identified mesenchymal-derived (MD) epithelial and transitional cells during the regenerative window and revealed a critical role for mesenchymal-epithelial transition (MET) in this process. Single-nucleus RNA sequencing further uncovered functional characteristics of these cells and highlighted WNT, BMP, and EPHA signaling as potential regulators of MET. These findings provide new insight into the cellular and molecular framework of endometrial regeneration and have important implications for diseases involving aberrant tissue repair.