PT - JOURNAL ARTICLE AU - Dah-Jiun Fu AU - Andrea J. De Micheli AU - Mallikarjun Bidarimath AU - Lora H. Ellenson AU - Benjamin D. Cosgrove AU - Andrea Flesken-Nikitin AU - Alexander Yu. Nikitin TI - PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium AID - 10.1101/853994 DP - 2019 Jan 01 TA - bioRxiv PG - 853994 4099 - http://biorxiv.org/content/early/2019/11/25/853994.short 4100 - http://biorxiv.org/content/early/2019/11/25/853994.full AB - Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells. However, their location remains debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here we show that cells expressing transcription factor PAX8 are the main contributor to the homeostatic regeneration of endometrial epithelium. In the uterus, based on a single-cell transcriptome and immunostaining analyses, PAX8 expression is limited to the endometrial epithelium. According to lineage tracing, PAX8 positive (PAX8+) epithelial cells are responsible for long-term maintenance of the epithelium. Furthermore, multicolor tracing shows that individual glands are formed by clonal expansion of cells labeling both glandular and luminal epithelial components. Inactivation of tumor suppressor genes Trp53 and Rb1 in PAX8+ cells but not FOXJ1+ cells leads to formation of neoplasms with features of serous endometrial carcinoma, the most aggressive type of human endometrial malignancy. Taken together, our results show that a progeny of single PAX8+ cells represent the main source of cyclical regeneration of the endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma, and suggest that PAX8+ cells represent the cell-of-origin of this neoplasm.