Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease.
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.
Bataille
Frauke
F
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Rohrmeier
Christian
C
Bates
Richard
R
Weber
Achim
A
Rieder
Florian
F
Brenmoehl
Julia
J
Strauch
Ulrike
U
Farkas
Stefan
S
Fürst
Alois
A
Hofstädter
Ferdinand
F
Schölmerich
Jürgen
J
Herfarth
Hans
H
Rogler
Gerhard
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D015820:Cadherins / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D017577:Cutaneous Fistula / Q000453:epidemiology / Q000209:etiology / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007412:Intestinal Fistula / Q000453:epidemiology / Q000209:etiology / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000473:pathology*; D008875:Middle Aged; D012016:Reference Values; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D055815:Young Adult
D015820:Cadherins