Cell Lineage Tracing Identifies Hormone-Regulated and Wnt-Responsive Vaginal Epithelial Stem Cells

• Published in: Cell reports (Cambridge) Vol. 30; no. 5; pp. 1463 - 1477.e7
• Main Authors: Ali, Ayesha, Syed, Shafiq M., Jamaluddin, M. Fairuz B., Colino-Sanguino, Yolanda, Gallego-Ortega, David, Tanwar, Pradeep S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-02-2020; Elsevier
• Subjects: Animals; Axin Protein - metabolism; beta Catenin - metabolism; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Self Renewal; Epithelial Cells - cytology; Female; Hormones - metabolism; Mice, Inbred C57BL; Models, Biological; organoids; Organoids - cytology; Regeneration; reproductive tract; RNA-Seq; sexually transmitted infections; single-cell sequencing; stem cells; Stem Cells - cytology; Stem Cells - metabolism; Vagina - cytology; Wnt; Wnt Proteins - metabolism; Wnt Signaling Pathway; β-catenin; β-catenin; stem cells; single-cell sequencing; sexually transmitted infections; organoids; reproductive tract; Wnt
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.003

The intact vaginal epithelium is essential for women’s reproductive health and provides protection against HIV and sexually transmitted infections. How this epithelium maintains itself remains poorly understood. Here, we used single-cell RNA sequencing (RNA-seq) to define the diverse cell populations in the vaginal epithelium. We show that vaginal epithelial cell proliferation is limited to the basal compartment without any obvious label-retaining cells. Furthermore, we developed vaginal organoids and show that the basal cells have increased organoid forming efficiency. Importantly, Axin2 marks a self-renewing subpopulation of basal cells that gives rise to differentiated cells over time. These cells are ovariectomy-resistant stem cells as they proliferate even in the absence of hormones. Upon hormone supplementation, these cells expand and reconstitute the entire vaginal epithelium. Wnt/β-catenin is essential for the proliferation and differentiation of vaginal stem cells. Together, these data define heterogeneity in vaginal epithelium and identify vaginal epithelial stem cells.
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•scRNA-seq analysis redefines vaginal epithelial cell hierarchy•Cd271+Axin2+ cells represent ovariectomy-resistant vaginal epithelial stem cells•These cells are responsible for vaginal epithelial homeostasis and regeneration•Cd271+Axin2+ cell-derived organoids mimic vaginal epithelium in vivo
Abnormalities in vaginal epithelium, the first line of defense against pathogens, are associated with sexually transmitted diseases and vaginal atrophy. Ali et al. show that CD271+Axin2+ basal cells are vaginal stem cells that are responsible for epithelial homeostasis and regeneration, providing fundamental insights into the maintenance of this epithelial barrier.