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 and hierarchy remain 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 describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome, and evaluate contribution of epithelial cells expressing transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8 positive (PAX8+) epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. 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, one of the most aggressive type of human endometrial malignancy. Taken together, our results show that a progeny of single PAX8+ cells represent the main regeneration source of the adult 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.

中文翻译：

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表达PAX8的细胞是成人子宫内膜上皮稳态再生的主要来源，并引起浆液性子宫内膜癌。

人类和小鼠的子宫内膜上皮具有周期性再生。预计这种再生是由组织干细胞确保的。然而，它们的位置和层次结构仍然存在争议。最近的许多研究表明小鼠子宫内膜上皮中存在干细胞。同时，据报道，该组织可以通过基质/间充质或骨髓细胞来源的干细胞再生。在这里，我们描述了小鼠子宫主要细胞类型和上皮子集转录组的单细胞转录组图谱，并评估了表达转录因子PAX8的上皮细胞对成体子宫内膜上皮的稳态再生和恶性转化的贡献。根据谱系追踪，PAX8 阳性 (PAX8+) 上皮细胞负责管腔上皮和腺上皮的长期维持。此外，多色追踪显示单个腺体和管腔上皮的连续区域是通过克隆细胞扩张形成的。PAX8+ 细胞中肿瘤抑制基因 Trp53 和 Rb1 的失活（而非 FOXJ1+ 细胞中的失活）会导致具有浆液性子宫内膜癌特征的肿瘤形成，浆液性子宫内膜癌是人类子宫内膜恶性肿瘤中最具侵袭性的类型之一。综上所述，我们的结果表明，单个 PAX8+ 细胞的后代代表了成人子宫内膜上皮的主要再生来源。他们还为 P53 和 RB 通路在浆液性子宫内膜癌发病机制中的关键作用提供了直接的实验遗传学证据，并表明 PAX8+ 细胞代表了这种肿瘤的细胞起源。