Mapping Uterine Remodeling from Pregnancy to a New Homeostatic State

Pregnancy drives uterine remodeling through rapid anatomical expansion and scar-free postpartum repair, yet how the organ reconstructs its cellular architecture after birth remains incompletely understood. Here, we present single-cell transcriptomic profiling of 698,631 cells derived from the whole mouse uterus across five distinct stages centered around parturition: Non-pregnant Control, late gestation (embryonic day 16.5), and postpartum days (PPD) 1, 7, and 30. We resolved 16 distinct cell lineages spanning epithelial, stromal, endothelial, and immune compartments. Although gross morphological involution occurs rapidly, with uterine horn length returning to baseline levels by PPD7, the underlying cellular architecture does not revert to its pre-pregnancy state. Tissue composition, transcriptional states, and intercellular signalling networks did not revert to their pre-pregnancy configurations. Instead, postpartum reconstruction proceeded through five sequential but overlapping transcriptional programs, with individual cells simultaneously extinguishing gestational programs and acquiring repair-associated states. By one month postpartum, the tissue adopts a reconfigured architecture that fails to fully reactivate the non-pregnant baseline, thus, establishing a novel homeostatic state. This work provides a foundation for delineating the specific organizational levels that fully recover following physiological injury versus those that establish new baseline set points.