Reconstructing Lineage Hierarchies of Mouse Uterus Epithelial Development Using Single-Cell Analysis

Wu, Bowen; Chen, An; Yu, Li; Yin, Zi; Gong, Lin; Li, Zhenli; Liu, Yixiao; Heng, Boon Chin; Zhang, Dandan; Zou, Xiaohui

doi:10.1016/j.stemcr.2017.05.022

Cited by 43 publications

(62 citation statements)

References 39 publications

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“…The scRNA-seq data further allows the analysis of potential growth factor/receptor interactions between the different cell types in the PND12 uterus. These results confirm and significantly extend the previous laser capture microdissection/microarray study (Filant and Spencer, 2013) and scRNA-seq analysis of developing uterine epithelial cells (Wu et al, 2017).…”

Section: Discussionsupporting

confidence: 90%

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

Potter

Mucenski

Mahoney

et al. 2018

Preprint

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statement: A single cell RNA-seq study of the developing mouse uterus defines cellular heterogeneities, lineage specific gene expression programs and perturbed pathways in Hox9,10,11 mutants. AbstractThe uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxc9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.

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Section: Discussionsupporting

confidence: 90%

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

Potter

Mucenski

Mahoney

et al. 2018

Preprint

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“…Our study discovered an unique subset of epithelial cells of the uterus with stem/progenitor property of proliferation, EMT and low hormone receptor expression, which was similar to the characteristics of the epithelial cell cluster we previous reported during the development of mice uterus that was also highly proliferative, EMT and low hormone receptor expression and located in the luminal layer of the uterus (Wu et al 2017).…”

Section: Our Atlas Highlighted a Emt Program In The Epithelial Subsetsupporting

confidence: 86%

“…As the advance of technology and development analysis pipelines, studies have come to the single cell level (Proserpio and Lonnberg 2016). One of our previous study on uterus epithelial development was based on single cell analysis (Wu et al 2017). A previous report compared the transcriptomics of endometrial stroma cells in vivo and in vitro by single cell RNA-seq (Krjutskov et al 2016).…”

Section: Our Atlas Provided the Most Detailed Cell Diversity Of The Umentioning

confidence: 99%

Cell atlas of human uterus

Liu

et al. 2018

Preprint

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The human uterus is a highly dynamic tissue that undergoes repeated damage repair and regeneration during the menstrual cycle, which make it ideal model to study tissue regeneration and pathological process. Stem/progenitors were speculated to be involved in the regeneration of endometrial epithelial and pathogenesis of endometriosis. But the identity, microenvironment and regulatory mechanisms of the uterus epithelial stem/progenitors in vivo remain unclear. Here, we dissected the cell heterogeneities of the full-thickness human uterus epithelial cells (11 clusters), stroma cells (6 clusters), endothelial cells (5 clusters), smooth muscle cells (2 clusters), myofibroblasts (2 clusters) and immune cells (6 clusters) from 2735 single cell by single cell RNA-seq. Further analysis identified a unique ciliated epithelial cell cluster showing characteristics of stem/progenitors with properties of epithelial-mesenchymal transition (EMT) that mainly localized in the upper functionalis of the endometrium. Ordering the cell subpopulations along the pseudo-space revealed cell clusters possess cellular states of stress, inflammation and apoptosis in the upper functionalis cellular ecosystem of the endometrium. Connectivity map between the human uterus subpopulations revealed potential inflammatory (cytokines and chemokines) and developmental (WNT, FGF, VEGF) signals within the upper functionalis cellular ecosystem of the endometrium, especially from other epithelial clusters, regulating cell plasticity of the EMT-epithelial clusters. This study reconstructed the heterogeneities, space-specific distribution and connectivity map of human uterus atlas, which would provide insight in the regeneration of uterus endometria and reference for the pathogenesis of uterus.

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“…An attempt to establish cell lineage hierarchy of the mouse uterus during development has been reported (Wu et al, 2017). Unfortunately, the study was focused only on CD326+ epithelial cells isolated by FACS and therefore did not allow identification of other epithelium-specific markers.…”

Section: Resultsmentioning

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.

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Reconstructing Lineage Hierarchies of Mouse Uterus Epithelial Development Using Single-Cell Analysis

Cited by 43 publications

References 39 publications

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

Cell atlas of human uterus

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

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