Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus

Jin, Shiying

doi:10.1073/pnas.1814597116

Cited by 69 publications

(72 citation statements)

References 40 publications

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“…Group 2 was characterized by preferential expression of Ltf and Foxa2 . Based on glandular-specific expression of FOXA2 ( Jin, 2019 ; Fig. 1 D), this group was annotated as the glandular epithelium.…”

Section: Resultsmentioning

confidence: 99%

“…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. By contrast, the second study reported that Axin2 + glandular cells can act as drivers of epithelial homeostasis and regeneration ( Syed et al, 2020 ).…”

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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Although the physiological and pathological changes in the endometrium during remodeling are well characterized, the cellular mechanisms that drive the programmed events of the endometrial tissue remodeling are still not completely understood. Recent studies provide evidence for endometrial stem cell (ESC) populations that contribute to endometrial regeneration and repair [14,15]. However, these studies have either used rodent models that does not experience menstrual shedding or artificial mouse models with administration and withdrawal of exogenous progesterone rather than the naturally menstruating women with declining hormone levels caused by the demise of corpus luteum.…”

Section: Introductionmentioning

confidence: 99%

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration

et al. 2020

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The human endometrium undergoes sequential phases of shedding of the upper functionalis zone during menstruation, followed by regeneration of the functionalis zone from the remaining basalis zone cells, and secretory differentiation under the influence of the ovarian steroid hormones estradiol (E2) and progesterone (P4). This massive tissue regeneration after menstruation is believed to arise from endometrial stromal and epithelial stem cells residing in the basal layer of the endometrium. Although many endometrial pathologies are thought to be associated with defects in these stem cells, studies on their identification and regulation are limited, primarily due to lack of easily accessible animal models, as these processes are unique to primates. Here we describe a robust new method to study endometrial regeneration and differentiation processes using human endometrial tissue slice cultures incorporating an air-liquid interface into a 3D matrix scaffold of type I collagen gel, allowing sustained tissue viability over three weeks. The 3D collagen gel-embedded endometrial tissue slices in a double-dish culture system responded to ovarian steroid hormones, mimicking the endometrial changes that occur in vivo during the menstrual cycle. These changes included the E2-induced upregulation of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in all endometrial compartments and were markedly suppressed by both P4 and E2 plus P4 treatments. There were also distinct changes in endometrial morphology after E2 and P4 treatments, including subnuclear vacuolation and luminal secretions in glands as well as decidualization of stromal cells, typical characteristics of a progestational endometrium in vivo. This long-term slice culture method provides a unique in vivo-like microenvironment for the study of human endometrial functions and remodeling during early pregnancy and experiments on stem cell populations involved in endometrial regeneration and remodeling. Furthermore, this model has the potential to enable studies on several endometrial diseases, including endometrial cancers and pregnancy complications associated with defects in endometrial remodeling.

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“…A number of recent studies have suggested location of stem cells in either the glandular (Kaitu'u-Lino et al, 2010) 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 et al, 2013;Valentijn et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium

Micheli

Bidarimath

et al. 2019

Preprint

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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 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.

show abstract

Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus

Cited by 69 publications

References 40 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

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration

PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium

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