Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.
Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.
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DOI：
10.1242/dmm.047035
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发表时间：
2020-10-30
影响因子：
4.3
通讯作者：
Nikitin AY
中科院分区：
文献类型：
--
作者：
Fu DJ;De Micheli AJ;Bidarimath M;Ellenson LH;Cosgrove BD;Flesken-Nikitin A;Nikitin AY
人类和小鼠子宫内膜上皮细胞具有周期性再生。预计这种再生是由组织干细胞确保的，但它们的位置和层次仍然存在争议。最近的一些研究表明，在小鼠子宫内膜上皮中存在干细胞。同时，据报道，这种组织可以通过基质/间充质或骨髓细胞来源的干细胞再生。在这里，我们描述了一个单细胞转录组图谱的主要细胞类型的小鼠子宫和上皮细胞亚群转录组和评估的贡献上皮细胞表达的转录因子PAX 8的稳态再生和恶性转化的成年子宫内膜上皮。根据谱系追踪，PAX 8+上皮细胞负责腔上皮和腺上皮的长期维持。此外，荧光示踪显示，单个腺体和腔上皮的连续区域是由克隆细胞扩增形成的。在PAX 8+细胞中，而不是在FOXJ 1+细胞中，肿瘤抑制基因Trp 53和Rb 1的失活导致形成具有浆液性子宫内膜癌特征的肿瘤，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PAX 8+细胞的后代代表了成年子宫内膜上皮再生的主要来源。它们还为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PAX 8+细胞代表了这种肿瘤的起源细胞。总结：该研究描述了小鼠子宫的单细胞转录组图谱，并表明PAX 8+细胞负责子宫内膜上皮的长期维持，并可能代表浆液性子宫内膜癌的起源细胞。
Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but 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 that 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 the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, 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 the tumor suppressor genes Trp53 and Rb1 in PAX8+ cells, but not in FOXJ1+ cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8+ cells represents the main source of regeneration 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. Summary: The study describes a single-cell transcriptomic atlas of the mouse uterus and shows that PAX8+ cells are responsible for long-term maintenance of endometrial epithelium and might represent the cell of origin of serous endometrial carcinoma.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
7.3
作者：
Cochrane, Dawn R.;Tessier-Cloutier, Basile;Huntsman, David G.
通讯作者：
Huntsman, David G.
影响因子：
64.8
作者：
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影响因子：
50.3
作者：
Berger AC;Korkut A;Kanchi RS;Hegde AM;Lenoir W;Liu W;Liu Y;Fan H;Shen H;Ravikumar V;Rao A;Schultz A;Li X;Sumazin P;Williams C;Mestdagh P;Gunaratne PH;Yau C;Bowlby R;Robertson AG;Tiezzi DG;Wang C;Cherniack AD;Godwin AK;Kuderer NM;Rader JS;Zuna RE;Sood AK;Lazar AJ;Ojesina AI;Adebamowo C;Adebamowo SN;Baggerly KA;Chen TW;Chiu HS;Lefever S;Liu L;MacKenzie K;Orsulic S;Roszik J;Shelley CS;Song Q;Vellano CP;Wentzensen N;Cancer Genome Atlas Research Network;Weinstein JN;Mills GB;Levine DA;Akbani R
通讯作者：
Akbani R
影响因子：
9.8
作者：
Ikoma, Tomomi;Kyo, Satoru;Inoue, Masaki
通讯作者：
Inoue, Masaki