Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary
| Autor: | Kim E. Barrett, Mamata Sivagnanam, Jocelyn Young, Barun Das, Kevin Okamoto, John Rabalais |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Malabsorption
Cellular differentiation Mutant Enteroendocrine cell RC799-869 IEC intestinal epithelial cell Pathogenesis Mice chemistry.chemical_compound UPR unfolded protein response Intestinal Mucosa Original Research EDM enteroid-derived monolayer MVID microvillous inclusion disease Gastroenterology qRT-PCR quantitative real-time polymerase chain reaction Cell Differentiation Epithelial cell adhesion molecule ELISA enzyme-linked immunosorbent assay Congenital Diarrhea Diseases of the digestive system. Gastroenterology Epithelial Cell Adhesion Molecule mRNA messenger RNA Cell biology EpCAM epithelial cell adhesion molecule ISC intestinal stem cell Defective Enterocyte Disease Susceptibility IHC immunohistochemistry Signal Transduction Enteroendocrine Cells CTE congenital tufting enteropathy PBS phosphate-buffered saline Notch signaling pathway CHGA chromogranin A Biology Permeability Intestinal Failure Malabsorption Syndromes medicine Animals Humans Intestinal epithelial cell differentiation Genetic Predisposition to Disease NICD Notch intracellular domain Hepatology Congenital Tufting Enteropathy medicine.disease Congenital tufting enteropathy TBS Tris-buffered saline Disease Models Animal PAS periodic acid-Schiff Glucose Gene Expression Regulation chemistry EpCAM Diarrhea Infantile Mutation Intestinal Cell Differentiation Cancer research H&E hematoxylin and eosin Biomarkers Immunostaining |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 4, Pp 1353-1371 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background & Aims Congenital tufting enteropathy (CTE) is an intractable diarrheal disease of infancy caused by mutations of epithelial cell adhesion molecule (EpCAM). The cellular and molecular basis of CTE pathology has been elusive. We hypothesized that the loss of EpCAM in CTE results in altered lineage differentiation and defects in absorptive enterocytes thereby contributing to CTE pathogenesis. Methods Intestine and colon from mice expressing a CTE-associated mutant form of EpCAM (mutant mice) were evaluated for specific markers by quantitative real-time polymerase chain reaction, Western blotting, and immunostaining. Body weight, blood glucose, and intestinal enzyme activity were also investigated. Enteroids derived from mutant mice were used to assess whether the decreased census of major secretory cells could be rescued. Results Mutant mice exhibited alterations in brush-border ultrastructure, function, disaccharidase activity, and glucose absorption, potentially contributing to nutrient malabsorption and impaired weight gain. Altered cell differentiation in mutant mice led to decreased enteroendocrine cells and increased numbers of nonsecretory cells, though the hypertrophied absorptive enterocytes lacked key features, causing brush border malfunction. Further, treatment with the Notch signaling inhibitor, DAPT, increased the numbers of major secretory cell types in mutant enteroids (graphical abstract 1). Conclusions Alterations in intestinal epithelial cell differentiation in mutant mice favor an increase in absorptive cells at the expense of major secretory cells. Although the proportion of absorptive enterocytes is increased, they lack key functional properties. We conclude that these effects underlie pathogenic features of CTE such as malabsorption and diarrhea, and ultimately the failure to thrive seen in patients. Graphical abstract |
| Databáze: | OpenAIRE |
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