Endometrial Axin2+ Cells Drive Epithelial Homeostasis, Regeneration, and Cancer following Oncogenic Transformation

Syed, Shafiq M.; Kumar, Manish; Ghosh, Arnab; Tomasetig, Florence; Ali, Ayesha; Whan, Renée; Alterman, Dariusz; Tanwar, Pradeep S.

doi:10.1016/j.stem.2019.11.012

Cited by 96 publications

(106 citation statements)

References 51 publications

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“…Recently, two studies based on cell lineage tracing with tamoxifen-controlled Cre expression have been published ( Jin, 2019 ; Syed et al, 2020 ). The first study used limited labeling and mathematical analysis in Krt19-Cre/ERT2 and FoxA2-Cre/ERT2 mice crossed with reporter mice ( Jin, 2019 ) and concluded that the stem cell population resides in the intersection zone between luminal and glandular epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…The first study used limited labeling and mathematical analysis in Krt19-Cre/ERT2 and FoxA2-Cre/ERT2 mice crossed with reporter mice ( Jin, 2019 ) and concluded that the stem cell population resides in the intersection zone between luminal and glandular epithelium. By contrast, the second study reported that Axin2 + glandular cells can act as drivers of epithelial homeostasis and regeneration ( Syed et al, 2020 ). Cell fate tracing was initiated at either diestrus ( Jin, 2019 ) or metestrus ( Syed et al, 2020 ), which complicates comparative interpretation of the results.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, the second study reported that Axin2 + glandular cells can act as drivers of epithelial homeostasis and regeneration ( Syed et al, 2020 ). Cell fate tracing was initiated at either diestrus ( Jin, 2019 ) or metestrus ( Syed et al, 2020 ), which complicates comparative interpretation of the results. Following of AXIN2 + cells was for periods ≤70 days for virgin mice.…”

Section: Discussionmentioning

confidence: 99%

“…A number of recent studies have suggested the location of stem cells in either the glandular ( Kaitu'u-Lino et al, 2010 ; Syed et al, 2020 ) or luminal ( Chan and Gargett, 2006 ; Huang et al, 2012 ; Jin, 2019 ) compartments of the mouse endometrial epithelium. In humans, such cells are commonly thought to be located in the basalis segment of the endometrial glands ( Nguyen et al, 2012 ; Patterson and Pru, 2013 ; Valentijn et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma

Micheli

Bidarimath

et al. 2020

Disease Models &Amp; Mechanisms

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma

Micheli

Bidarimath

et al. 2020

Disease Models &Amp; Mechanisms

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“…Endometrial carcinoma (EC), which results from aberrant regeneration in terms of excessive growth of endometrial glands [1], accounts for 4.4% of carcinoma cases among women in 2018 [2] with more than 60,000 cases estimated in the United States in 2019 [3]. As for endometrial precancerous lesions including atypical hyperplasia or endometrial intraepithelial neoplasia and well-differentiated cancer, hysterectomy would not be a feasible and effective optimal choice for them and conservative treatment to preserve fertility for young patients is becoming significantly essential.…”

Section: Introductionmentioning

confidence: 99%

Screening and identification of MSX1 for predicting progestin resistance in endometrial cancer

Yang

Cui

Huang

et al. 2020

Preprint

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Background: Progestin resistance is a critical obstacle for endometrial conservative therapy. Therefore, the studies to acquire a more comprehensive understanding of the mechanisms and specific biomarkers to predict progestin resistance are very important. However, the pivotal roles of essential molecules of progestin resistance are still unexplored.Methods: We downloaded GSE121367 with gene expression profiles of medroxyprogesterone acetate (MPA) resistant and sensitive cell lines from the GEO database. The "limma" R language package was applied to identify differentially expressed genes (DEGs). Gene ontology and pathway enrichment analysis was performed through the database of DAVID. Meanwhile, we conducted GSEA analysis to identify pathway enrichments. Protein-protein interaction construction of top genes was conducted to screen hub genes by STRING and visualized in Cytoscape. A high connectivity degree of hub genes were picked out to perform the differential expression, methylation validation and overall survival analysis in the Gene Expression Profiling Interactive Analysis database, Human Protein Atlas database and Kaplan-Meier plotter online tool, respectively. In addition, microRNAs and upstream transcription factors of hub genes were predicted by miRTarBase and Network Analyst database.Results: A total number of 3282 differentially expressed genes were identified. Functional enrichment analysis demonstrated that these genes were mostly enriched in negative regulation of DNA binding, chronic inflammatory response and cell adhesion molecules pathway. We screened out ten hub genes including CDH1, JAG1, PTGES, EPCAM, CNTNAP2, TBX1, MSX1, KRT19, OAS1 and DAB2 among different groups. The genomic alteration rates of hub genes were low based on the current uterine corpus endometrial carcinoma sample sets. Their relevant microRNA and transcription factor were detected and has-miR-335-5p, has-miR-124-3p, MAZ and TFDP1 were the most prominent. The methylation status of CDH1, JAG1, EPCAM and MSX1 were decreased, corresponding to their high protein expression in endometrial cancers, which also indicated better overall survival. The homeobox protein of MSX1 showed significantly tissue specificity.Conclusions: Our study identified ten hub genes associated with progestin resistance of endometrial cancer and screened out the gene of MSX1 which promised to be the specific indicator. This would

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An injectable gelatin/sericin hydrogel loaded with human umbilical cord mesenchymal stem cells for the treatment of uterine injury

Chen

et al. 2022

Bioengineering & Transla Med

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Abnormal endometrial receptivity is a major cause of the failure of embryo transplantation, which may lead to infertility, adverse pregnancy, and neonatal outcomes. While hormonal treatment has dramatically improved the fertility outcomes in women with endometriosis, a substantial unmet need persists in the treatment. In this study, methacrylate gelatin (GelMA) and methacrylate sericin (SerMA) hydrogel with human umbilical cord mesenchymal stem cells (HUMSC) encapsulation was designed for facilitating endometrial regeneration and fertility restoration through in situ injection. The presented GelMA/10%SerMA hydrogel showed appropriate swelling ratio, good mechanical properties, and degradation stability. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell encapsulation ability of HUMSC. Further in vivo experiments demonstrated that GelMA/SerMA@HUMSC hydrogel could increase the thickness of endometrium and improve the endometrial interstitial fibrosis. Moreover, regenerated endometrial tissue was more receptive to transfer embryos. Summary, we believed that GelMA/SerMA@HUMSC hydrogel will hold tremendous promise to repair or regenerate damaged endometrium.

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Endometrial Axin2+ Cells Drive Epithelial Homeostasis, Regeneration, and Cancer following Oncogenic Transformation

Abstract: Highlights d Endometrial epithelium self-renews throughout life d Axin2 marks long-lived bipotent stem cells residing at the base of glands d Axin2 + cells fuel endometrial epithelial growth and regeneration d Mutant Axin2 + cells lead to endometrial carcinogenesis

Cited by 96 publications

References 51 publications

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

Screening and identification of MSX1 for predicting progestin resistance in endometrial cancer

An injectable gelatin/sericin hydrogel loaded with human umbilical cord mesenchymal stem cells for the treatment of uterine injury

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