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Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis.

Scharl M, Huber N, Lang S, Fürst A, Jehle E, Rogler G - Clin Transl Med (2015)

Bottom Line: In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT).We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients.We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn's disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.

Methods: Human colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques.

Results: In fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.

Conclusions: We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis.

No MeSH data available.


Related in: MedlinePlus

Subepithelial cells in and around fibrotic areas express α-SMA. Representative images show α-SMA (A) and van-Gieson (B) staining in corresponding tissue sections. Magnification: 10-fold or 40-fold, respectively. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
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Fig7: Subepithelial cells in and around fibrotic areas express α-SMA. Representative images show α-SMA (A) and van-Gieson (B) staining in corresponding tissue sections. Magnification: 10-fold or 40-fold, respectively. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.

Mentions: We next assessed the expression of E-cadherin which is usually located in adherens junctions of epithelial cell layers, connecting adjacent cells. We found strong E-cadherin staining in the intestinal epithelial layer (Figure 6A). However, we also detected expression of E-cadherin in a number of subepithelial cells in and around fibrotic areas (Figure 6B + C). Further, we found a large number of α-SMA positive cells in fibrotic areas of intestinal tissue specimens from CD patients (Figures 7A-B). This co-incidence of mesenchymal and epithelial markers in areas of fibrotic tissue strongly supports an involvement of EMT in the pathogenesis of CD-associated fibrosis.Figure 6


Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis.

Scharl M, Huber N, Lang S, Fürst A, Jehle E, Rogler G - Clin Transl Med (2015)

Subepithelial cells in and around fibrotic areas express α-SMA. Representative images show α-SMA (A) and van-Gieson (B) staining in corresponding tissue sections. Magnification: 10-fold or 40-fold, respectively. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384762&req=5

Fig7: Subepithelial cells in and around fibrotic areas express α-SMA. Representative images show α-SMA (A) and van-Gieson (B) staining in corresponding tissue sections. Magnification: 10-fold or 40-fold, respectively. All analysed patient samples showed comparable staining characteristics when compared to samples from non-affected controls.
Mentions: We next assessed the expression of E-cadherin which is usually located in adherens junctions of epithelial cell layers, connecting adjacent cells. We found strong E-cadherin staining in the intestinal epithelial layer (Figure 6A). However, we also detected expression of E-cadherin in a number of subepithelial cells in and around fibrotic areas (Figure 6B + C). Further, we found a large number of α-SMA positive cells in fibrotic areas of intestinal tissue specimens from CD patients (Figures 7A-B). This co-incidence of mesenchymal and epithelial markers in areas of fibrotic tissue strongly supports an involvement of EMT in the pathogenesis of CD-associated fibrosis.Figure 6

Bottom Line: In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT).We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients.We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn's disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.

Methods: Human colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques.

Results: In fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts.

Conclusions: We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis.

No MeSH data available.


Related in: MedlinePlus