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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

The transcription factor SLUG is expressed in the nuclei of mesenchymal cells in fibrotic areas. (A-D) Representative images demonstrate considerable SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. SLUG is visible in the nuclei of fibroblast-like cells (black arrows) indicative for transcriptionally active SLUG protein. The insert in (A) demonstrates van-Gieson staining. 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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Fig4: The transcription factor SLUG is expressed in the nuclei of mesenchymal cells in fibrotic areas. (A-D) Representative images demonstrate considerable SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. SLUG is visible in the nuclei of fibroblast-like cells (black arrows) indicative for transcriptionally active SLUG protein. The insert in (A) demonstrates van-Gieson staining. 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 investigated the expression of Snail transcription factor family members, namely SLUG and Snail1 in fibrotic intestine of CD patients. We found strong SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. Of notice, SLUG was often visible in the nuclei of fibroblast-like cells indicative for transcriptionally active SLUG protein (Figure 4A-D). Increased expression and nuclear translocation of SLUG are often correlated with the onset of EMT and our finding provides therefore a possible mechanistic explanation how EMT-associated events in fibrotic areas could be mediated on a transcriptional level. Slug staining was almost completely absent in non-IBD control patients (data not shown). Interestingly, the transcription factor SNAIL1, was neither detectable in non-IBD control patients nor in fibrotic regions of CD patients (data not shown).Figure 4


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)

The transcription factor SLUG is expressed in the nuclei of mesenchymal cells in fibrotic areas. (A-D) Representative images demonstrate considerable SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. SLUG is visible in the nuclei of fibroblast-like cells (black arrows) indicative for transcriptionally active SLUG protein. The insert in (A) demonstrates van-Gieson staining. 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
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getmorefigures.php?uid=PMC4384762&req=5

Fig4: The transcription factor SLUG is expressed in the nuclei of mesenchymal cells in fibrotic areas. (A-D) Representative images demonstrate considerable SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. SLUG is visible in the nuclei of fibroblast-like cells (black arrows) indicative for transcriptionally active SLUG protein. The insert in (A) demonstrates van-Gieson staining. 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 investigated the expression of Snail transcription factor family members, namely SLUG and Snail1 in fibrotic intestine of CD patients. We found strong SLUG staining in fibroblast-like cells of fibrotic areas of colonic tissue specimens derived from CD patients. Of notice, SLUG was often visible in the nuclei of fibroblast-like cells indicative for transcriptionally active SLUG protein (Figure 4A-D). Increased expression and nuclear translocation of SLUG are often correlated with the onset of EMT and our finding provides therefore a possible mechanistic explanation how EMT-associated events in fibrotic areas could be mediated on a transcriptional level. Slug staining was almost completely absent in non-IBD control patients (data not shown). Interestingly, the transcription factor SNAIL1, was neither detectable in non-IBD control patients nor in fibrotic regions of CD patients (data not shown).Figure 4

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