A perivascular niche supports endometrial epithelial regeneration

Endometrial regeneration is essential for reproductive cycles and pregnancies, allowing the endometrium to undergo repair and renewal after menstruation and parturition. Epithelial cells lining the uterine cavity are shed during each cycle, although remnant luminal and glandular epithelial cells can regenerate the lumen lining. It is presumed that adult stem/progenitor cells in the uterine stroma also contribute to this regeneration. However, the specific cell type(s) and the underlying mechanisms have not been determined. Herein, we use genetic lineage tracing assays in mice to identify Nestin + perivascular cells as active contributors to epithelial regeneration. Notch signaling maintains Nestin + perivascular cells in a quiescent state but these cells re-enter the cell cycle and differentiate into epithelial cells via estrogen-stimulated suppression of Notch signaling dependent on estrogen receptor alpha (ERα/ESR1). These findings demonstrate that perivascular cells support epithelial regeneration and reveal a mechanism regulating the quiescence and activation of uterine perivascular cells.