ALDH1A1+ cells are endometrial progenitors contributing to regeneration and endometriosis [mouse]

Endometrial stem cells and their regenerative properties are implicated in the pathogenesis of endometriosis. Using single-cell RNA sequencing of the adult mouse endometrial epithelium, we identified a sub-population of aldehyde dehydrogenase 1a1+ (Aldh1a1+) stem-like cells that co-expresses stemness genes (Lgr5, Axin2) and lack proliferative markers (Top2a, Mki67). Using an Aldh1a1cre/ERT2;ROSA26tdTomato reporter mouse, we found that Aldh1a1+ cells give rise to long-lived endometrial cells and contribute to post-partum endometrial repair. Selective ablation of ALDH1A1+ cells with diphtheria toxin (DT) in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased glands and FOXA2 expression in vivo. Mouse and human ALDHHI endometrial cells had higher organoid formation capacity and stem-like gene signatures than ALDHLO cells. Ectopic lesion-derived organoids showed higher ALDH activity than patient-matched eutopic cells and displayed enriched pro-inflammatory, stemness, and ciliated cell transcriptomes. Here we provide evidence that ALDH1A1+ cells display progenitor/stem cell characteristics in the endometrium and contribute to the pathology of endometriosis.