Abstract

Menstruation and pregnancy disrupt substantial proportions of the uterine lining (endometrium). These breaches impose an immense regenerative burden on the luminal epithelium that lines the uterine cavity, which is proposed to be replenished by cells residing in adjoining epithelial glands. Here, we show that the luminal epithelium and glandular epithelium are maintained by separate progenitor populations during homeostasis, induced menstruation, pregnancy, and postpartum repair in mice. These data challenge the gland-centric model of regeneration during these physiological events, although we find that gland cells can resurface the tissue after chemical ablation. Our data indicate that during menstruation, the luminal epithelium bypasses the need for gland contributions by undergoing extensive expansion and morphogenesis to re-epithelialize stromal surfaces as the tissue breaks down. Analogous morphogenesis occurs during gestational remodeling, revealing luminal epithelial expansion as a unifying mechanism enabling simultaneous stromal disruption and re-epithelialization, which may underlie the endometrium's remarkable resilience to fibrosis.