Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary
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 i...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001302 |
| _version_ | 1818744033336360960 |
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| author | Barun Das Kevin Okamoto John Rabalais Jocelyn A. Young Kim E. Barrett Mamata Sivagnanam |
| author_facet | Barun Das Kevin Okamoto John Rabalais Jocelyn A. Young Kim E. Barrett Mamata Sivagnanam |
| author_sort | Barun Das |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T02:37:52Z |
| format | Article |
| id | doaj.art-5801d138dcd94c91adee3f5dcbc1d252 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-18T02:37:52Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-5801d138dcd94c91adee3f5dcbc1d2522022-12-21T21:23:44ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112413531371Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummaryBarun Das0Kevin Okamoto1John Rabalais2Jocelyn A. Young3Kim E. Barrett4Mamata Sivagnanam5Department of Pediatrics, University of California, San Diego, La Jolla, CaliforniaDepartment of Pediatrics, University of California, San Diego, La Jolla, CaliforniaDepartment of Pediatrics, University of California, San Diego, La Jolla, CaliforniaDepartment of Pediatrics, University of California, San Diego, La Jolla, California; Department of Pediatrics, Rady Children’s Hospital, San Diego, CaliforniaDepartment of Medicine, University of California, San Diego, La Jolla, CaliforniaDepartment of Pediatrics, University of California, San Diego, La Jolla, California; Department of Pediatrics, Rady Children’s Hospital, San Diego, California; Correspondence Address correspondence to: Mamata Sivagnanam, MD, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, 9500 Gilman Drive, La Jolla, CA 92093. fax: 858-967-8917.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.http://www.sciencedirect.com/science/article/pii/S2352345X21001302Congenital Tufting EnteropathyIntestinal Cell DifferentiationIntestinal FailureEpCAMDefective EnterocyteCongenital Diarrhea |
| spellingShingle | Barun Das Kevin Okamoto John Rabalais Jocelyn A. Young Kim E. Barrett Mamata Sivagnanam Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary Cellular and Molecular Gastroenterology and Hepatology Congenital Tufting Enteropathy Intestinal Cell Differentiation Intestinal Failure EpCAM Defective Enterocyte Congenital Diarrhea |
| title | Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary |
| title_full | Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary |
| title_fullStr | Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary |
| title_full_unstemmed | Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary |
| title_short | Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting EnteropathySummary |
| title_sort | aberrant epithelial differentiation contributes to pathogenesis in a murine model of congenital tufting enteropathysummary |
| topic | Congenital Tufting Enteropathy Intestinal Cell Differentiation Intestinal Failure EpCAM Defective Enterocyte Congenital Diarrhea |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21001302 |
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