scholarly journals Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3001032
Author(s):  
Michael David Brügger ◽  
Tomas Valenta ◽  
Hassan Fazilaty ◽  
George Hausmann ◽  
Konrad Basler
Keyword(s):  
Epithelial Cells ◽  
Growth Factor Receptor ◽  
Morphogenetic Protein ◽  
Wnt Ligands ◽  
Unbiased Manner ◽  
Low Levels ◽  
Cell Transcriptome ◽  
Canonical Wnt ◽  
Single Cell Transcriptome ◽  
Murine Colon

Despite recent progress in recognizing the importance of mesenchymal cells for the homeostasis of the intestinal system, the current picture of how these cells communicate with the associated epithelial layer remains unclear. To describe the relevant cell populations in an unbiased manner, we carried out a single-cell transcriptome analysis of the adult murine colon, producing a high-quality atlas of matched colonic epithelium and mesenchyme. We identify two crypt-associated colonic fibroblast populations that are demarcated by different strengths of platelet-derived growth factor receptor A (Pdgfra) expression. Crypt-bottom fibroblasts (CBFs), close to the intestinal stem cells, express low levels of Pdgfra and secrete canonical Wnt ligands, Wnt potentiators, and bone morphogenetic protein (Bmp) inhibitors. Crypt-top fibroblasts (CTFs) exhibit high Pdgfra levels and secrete noncanonical Wnts and Bmp ligands. While the Pdgfralow cells maintain intestinal stem cell proliferation, the Pdgfrahigh cells induce differentiation of the epithelial cells. Our findings enhance our understanding of the crosstalk between various colonic epithelial cells and their associated mesenchymal signaling hubs along the crypt axis—placing differential Pdgfra expression levels in the spotlight of intestinal fibroblast identity.

scholarly journals Single cell transcriptome atlas of mouse mammary epithelial cells across development

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Bhupinder Pal ◽  
Yunshun Chen ◽  
Michael J. G. Milevskiy ◽  
François Vaillant ◽  
Lexie Prokopuk ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Single Cell ◽  
Developmental Stages ◽  
Mammary Epithelial Cells ◽  
Expression Profiles ◽  
Single Cells ◽  
Chromatin Accessibility ◽  
Mammary Epithelial ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract Background Heterogeneity within the mouse mammary epithelium and potential lineage relationships have been recently explored by single-cell RNA profiling. To further understand how cellular diversity changes during mammary ontogeny, we profiled single cells from nine different developmental stages spanning late embryogenesis, early postnatal, prepuberty, adult, mid-pregnancy, late-pregnancy, and post-involution, as well as the transcriptomes of micro-dissected terminal end buds (TEBs) and subtending ducts during puberty. Methods The single cell transcriptomes of 132,599 mammary epithelial cells from 9 different developmental stages were determined on the 10x Genomics Chromium platform, and integrative analyses were performed to compare specific time points. Results The mammary rudiment at E18.5 closely aligned with the basal lineage, while prepubertal epithelial cells exhibited lineage segregation but to a less differentiated state than their adult counterparts. Comparison of micro-dissected TEBs versus ducts showed that luminal cells within TEBs harbored intermediate expression profiles. Ductal basal cells exhibited increased chromatin accessibility of luminal genes compared to their TEB counterparts suggesting that lineage-specific chromatin is established within the subtending ducts during puberty. An integrative analysis of five stages spanning the pregnancy cycle revealed distinct stage-specific profiles and the presence of cycling basal, mixed-lineage, and 'late' alveolar intermediates in pregnancy. Moreover, a number of intermediates were uncovered along the basal-luminal progenitor cell axis, suggesting a continuum of alveolar-restricted progenitor states. Conclusions This extended single cell transcriptome atlas of mouse mammary epithelial cells provides the most complete coverage for mammary epithelial cells during morphogenesis to date. Together with chromatin accessibility analysis of TEB structures, it represents a valuable framework for understanding developmental decisions within the mouse mammary gland.

scholarly journals Single-Cell Transcriptome Sequencing and Proteomics Reveal Neonatal Ileum Dynamic Developmental Potentials

mSystems ◽  
2021 ◽  
Author(s):  
Qingshi Meng ◽  
Liang Chen ◽  
Bohui Xiong ◽  
Beining Kang ◽  
Pengfei Zhang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Secretory Cells ◽  
Protein Signaling ◽  
Morphogenetic Protein ◽  
Undifferentiated Cells ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
G Protein Coupled ◽  
Enterocyte Differentiation

We found previously unknown neonatal ileum developmental potentials: specific increases in undifferentiated cells, unique enterocyte differentiation, and time dependent reduction in secretory cells. Specific transcriptional factors (TFs), ligand-receptor pairs, G protein-coupled receptors, transforming growth factor β, bone morphogenetic protein signaling pathways, and the gut mucosal microbiota are involved in this process.

scholarly journals Single-cell Transcriptome Analysis Reveals an Anomalous Epithelial Variation and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease

2020 ◽  
Author(s):  
Naoaki Watanabe ◽  
Jun Nakayama ◽  
Yu Fujita ◽  
Yutaro Mori ◽  
Tsukasa Kadota ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Epithelial Cells ◽  
Single Cell ◽  
Transcriptome Analysis ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Never Smokers ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractChronic obstructive pulmonary disease (COPD) is a progressive disease that obstructs the airflow from the lungs, and tobacco smoking is the major cause of COPD. Here, we applied single-cell RNA sequencing to analyze COPD pathogenesis in COPD patients, non-COPD smokers and never-smokers and investigated the disease progression at single-cell resolution. By single-cell transcriptome analysis, COPD was characterized by shifts in the stromal, immune system and epithelial cell compositions. While epithelial components in never-smokers were relatively uniform, the smoker groups presented with extensive heterogeneity in epithelial cells, particularly in the alveolar type II (AT2) lineages. We identified a subpopulation of AT2 epithelial cells that emerged in smokers, such as COPD patients, and specifically expressed a series of chemokines and PD-L1. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred increased intercellular networks of inflammatory AT2 cells with immune and stromal cell populations. Thus, our analysis reveals a unique cellular differentiation pathway and function underlying the biological and clinical characteristics of COPD pathogenesis.

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

2019 ◽  
Author(s):  
Dah-Jiun Fu ◽  
Andrea J. De Micheli ◽  
Mallikarjun Bidarimath ◽  
Lora H. Ellenson ◽  
Benjamin D. Cosgrove ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Endometrial Carcinoma ◽  
Marrow Cell ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Pax8 Expression ◽  
Endometrial Epithelium ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractHumans 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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