Molecular signature of human endometrial stem/progenitor cells at the single-cell level

Human endometrium sheds and regenerates each month during the menstrual cycle. N-cadherin⁺ (CDH2) glandular epithelial progenitors and SUSD2⁺ mesenchymal stem cells (MSCs) and their niches have been identified, but their signaling interactions remain unknown. SSEA1⁺ epithelial cells resurface the endometrium, generating a new luminal epithelium each cycle. Using these markers, we characterized the gene expression of human endometrial stem/progenitor cell-enriched populations derived from fluorescence-activated cell sorting (FACS)-sorted hysterectomy endometrium by single-cell RNA sequencing (scRNA-seq). Two of 10 epithelial clusters contained CDH2⁺SOX9⁺ cells with high TRH and IHH expressions. N-cadherin and IHH, and SSEA1 and Hedgehog co-receptor BOC immunoco-localized in the basal layer of endometrial glands, from which the new functional layer glands regenerate each menstrual cycle. Two of six mesenchymal clusters contained SUSD2⁺ MSCs, one with high MUSTN1 expression. Epithelial progenitors and endometrial MSCs transitioned to their respective progeny. We provide new insights into the human endometrial stem/progenitor cell signaling pathways and niche interactions regulating their function.