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Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease


Bataille, F; Rohrmeier, C; Bates, R; Weber, A; Rieder, F; Brenmoehl, J; Strauch, U; Farkas, S; Fürst, Alois; Hofstädter, F; Schölmerich, J; Herfarth, H; Rogler, G (2008). Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease. Inflammatory Bowel Diseases, 14(11):1514-1527.

Abstract

BACKGROUND: The pathogenesis of fistulae in Crohn's disease (CD) patients is barely understood. We recently showed that more than two-thirds of CD fistulae are covered with flat, mesenchymal-like cells (transitional cells [TC]) forming a patchy basement membrane. Epithelial-to-mesenchymal transition (EMT) is a process of reprogramming epithelial cells, allowing them to migrate more effectively and giving epithelial cells an "invasive" potential. EMT has been suggested to be crucial in fibrosis found in different tissues and diseases. We therefore investigated whether EMT could be involved in the pathogenesis of fistulae formation in CD. METHODS: In all, 18 perianal fistulae, 2 enteroenteric, and 1 enterovesical fistulae from 17 CD patients were analyzed. In addition 2 perianal fistulae of non-CD patients were studied. Hematoxylin and eosin staining, immunohistochemistry for the expression of cytokeratins 8 and 20, beta6-integrin, E-cadherin, beta-catenin, vimentin, and TGF-beta1 and 2 were performed according to standard techniques. RESULTS: The TC covering perianal or enteroenteric fistulae were strongly positive for cytokeratins 8 and 20 but negative for vimentin, indicating their epithelial origin. beta6-Integrin and TGF-beta had the highest staining intensities in the transitional zone between the epithelium and the TC. Expression of junctional proteins such as E-cadherin was reduced in TC as compared to regular fistulae epithelium. In addition, a translocation of beta-catenin from the membrane to the cytoplasm was observed. CONCLUSIONS: Our data for the first time indicate an expression pattern of epithelial and mesenchymal markers in TC associated with fistulae formation that is characteristic for EMT. Studying the pathways of EMT during intestinal fistulae formation may help to develop new therapeutic strategies.

BACKGROUND: The pathogenesis of fistulae in Crohn's disease (CD) patients is barely understood. We recently showed that more than two-thirds of CD fistulae are covered with flat, mesenchymal-like cells (transitional cells [TC]) forming a patchy basement membrane. Epithelial-to-mesenchymal transition (EMT) is a process of reprogramming epithelial cells, allowing them to migrate more effectively and giving epithelial cells an "invasive" potential. EMT has been suggested to be crucial in fibrosis found in different tissues and diseases. We therefore investigated whether EMT could be involved in the pathogenesis of fistulae formation in CD. METHODS: In all, 18 perianal fistulae, 2 enteroenteric, and 1 enterovesical fistulae from 17 CD patients were analyzed. In addition 2 perianal fistulae of non-CD patients were studied. Hematoxylin and eosin staining, immunohistochemistry for the expression of cytokeratins 8 and 20, beta6-integrin, E-cadherin, beta-catenin, vimentin, and TGF-beta1 and 2 were performed according to standard techniques. RESULTS: The TC covering perianal or enteroenteric fistulae were strongly positive for cytokeratins 8 and 20 but negative for vimentin, indicating their epithelial origin. beta6-Integrin and TGF-beta had the highest staining intensities in the transitional zone between the epithelium and the TC. Expression of junctional proteins such as E-cadherin was reduced in TC as compared to regular fistulae epithelium. In addition, a translocation of beta-catenin from the membrane to the cytoplasm was observed. CONCLUSIONS: Our data for the first time indicate an expression pattern of epithelial and mesenchymal markers in TC associated with fistulae formation that is characteristic for EMT. Studying the pathways of EMT during intestinal fistulae formation may help to develop new therapeutic strategies.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:November 2008
Deposited On:23 Dec 2008 11:34
Last Modified:05 Apr 2016 12:45
Publisher:Wiley-Blackwell
ISSN:1078-0998
Additional Information:The attached file is a preprint (accepted version) of an article published in Inflammatory Bowel Diseases. Full text at http://www3.interscience.wiley.com/cgi-bin/fulltext/120775691/PDFSTART
Publisher DOI:10.1002/ibd.20590
PubMed ID:18626977
Permanent URL: http://doi.org/10.5167/uzh-9029

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