Mesenchymal-epithelial transition supports rapid repair of the endometrial epithelium during postpartum uterine regeneration

Postpartum endometrial re-epithelialization is vital for uterine homeostasis and fertility, but mechanisms of this process are poorly understood. Using lineage-tracing mice and single-nucleus RNA-sequencing, we detail the process of mesenchymal-epithelial transition (MET) in endometrial re-epithelialization. Mesenchymal-derived (MD) epithelial cells arise quickly during repair and express genes related to cell adhesion, cytoskeletal remodeling, and epithelial barrier function. Nearing completion of repair, MD epithelial cells undergo apoptosis and are replaced by non-MD epithelial cells. We identified “transitional cells” that migrate towards and incorporate into the epithelium, signifying active MET. MET-associated genes were upregulated in MD epithelial and transitional cells. WNT and EPHA signaling were identified as candidate regulators of MET. These findings demonstrate MET as a mechanism to rapidly restore the endometrial epithelium during postpartum repair. Perturbations in MET may contribute to endometrial pathologies, underscoring the importance of understanding mesenchymal-epithelial plasticity in normal and disease states. Postpartum uterine repair involves mesenchymal-epithelial transition (MET), where stromal cells become epithelial cells to rapidly restore the endometrial lining before being replaced. This work highlights MET’s role in endometrial health and disease.