دورية أكاديمية
Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential.
| العنوان: | Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential. |
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| المؤلفون: | Klochkova A; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Karami AL; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Fuller AD; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Parham LR; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Panchani SR; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Natarajan S; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Jackson JL; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Mu A; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Tan Y; Fox Chase Cancer Center, Philadelphia, Pennsylvania., Cai KQ; Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Klein-Szanto AJ; Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Muir AB; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Tétreault MP; Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Graña X; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Hamilton KE; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Whelan KA; Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania. Electronic address: kelly.whelan@temple.edu. |
| المصدر: | Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2024; Vol. 18 (1), pp. 15-40. Date of Electronic Publication: 2024 Mar 05. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Gastroenterological Association Country of Publication: United States NLM ID: 101648302 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-345X (Electronic) Linking ISSN: 2352345X NLM ISO Abbreviation: Cell Mol Gastroenterol Hepatol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Gastroenterological Association, [2015]- |
| مواضيع طبية MeSH: | Autophagy* , Cell Proliferation* , Homeostasis* , Mice, Knockout* , Organoids*/metabolism, Animals ; Mice ; Esophagus/pathology ; Esophagus/cytology ; Esophagus/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/drug effects ; Autophagy-Related Protein 7/metabolism ; Autophagy-Related Protein 7/genetics ; 4-Nitroquinoline-1-oxide ; Cell Self Renewal ; Esophageal Mucosa/pathology ; Esophageal Mucosa/metabolism ; Esophageal Mucosa/cytology ; Single-Cell Analysis |
| مستخلص: | Background & Aims: Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. Methods: We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. Results: Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-ID High ) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-ID Low ). RNA sequencing suggested increased autophagy in Cyto-ID High esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-ID Low and Cyto-ID High cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-ID High group. Ki67 expression was also increased in organoids generated by Cyto-ID High cells, including in basal cells localized beyond the outermost cell layer. Conclusions: Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Update of: bioRxiv. 2023 Sep 22:2023.09.20.558614. doi: 10.1101/2023.09.20.558614. (PMID: 37781581) |
| معلومات مُعتمدة: | R03 DK118304 United States DK NIDDK NIH HHS; R01 DK124369 United States DK NIDDK NIH HHS; T32 GM142606 United States GM NIGMS NIH HHS; R03 CA216134 United States CA NCI NIH HHS; R01 DK116988 United States DK NIDDK NIH HHS; R01 DK124266 United States DK NIDDK NIH HHS; P30 CA006927 United States CA NCI NIH HHS; F31 DK124956 United States DK NIDDK NIH HHS; R01 DK121159 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: ATG7; Autophagy; Basal Cell Dynamics; Esophageal Epithelium; Esophageal Progenitor Cells |
| المشرفين على المادة: | EC 6.2.1.45 (Autophagy-Related Protein 7) 56-57-5 (4-Nitroquinoline-1-oxide) 0 (Atg7 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240307 Date Completed: 20240619 Latest Revision: 20240728 |
| رمز التحديث: | 20240728 |
| مُعرف محوري في PubMed: | PMC11126828 |
| DOI: | 10.1016/j.jcmgh.2024.02.018 |
| PMID: | 38452871 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 2352-345X |
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| DOI: | 10.1016/j.jcmgh.2024.02.018 |