Abstract
Intestinal fibrosis is a major complication of Crohn disease (CD), but the precise mechanism by which it occurs is incompletely understood. As a result, specific therapies to halt or even reverse fibrosis have not been explored. Here, we evaluated the contribution of epithelial to mesenchymal transition (EMT) to intestinal fibrosis associated with a mouse model of CD and also human inflammatory bowel disease. Mice administered intrarectal 2,4,6-trinitrobenzene sulfonic acid (TNBS) develop inflammation and fibrosis that resembles CD both histologically and by immunologic profile. We utilized this model to molecularly probe the contribution of EMT to intestinal fibrosis. Additionally, we utilized double-transgenic VillinCre;R26Rosa-lox-STOP-lox-LacZ mice, in which removal of the STOP cassette by Cre recombinase in villin(+) intestinal epithelial cells activates permanent LacZ expression, to lineage trace epithelial cells that might undergo EMT upon TNBS administration. TNBS-induced fibrosis is associated with the presence of a significant number of cells that express both epithelial and mesenchymal markers. In the lineage tagged transgenic mice, the appearance of LacZ(+) cells that also express the fibroblast marker FSP1 unequivocally demonstrates EMT. Transforming growth factor (TGF)-beta1, a known inducer of EMT in epithelial cells, induces EMT in rat intestinal epithelial cells in vitro, and bone morphogenic protein-7, an antagonist of TGF-beta1, inhibits EMT and fibrosis both in vitro and in the TNBS-treated mice. Our study demonstrates that EMT contributes to intestinal fibrosis associated with the TNBS-induced model of Crohn colitis and that inhibition of TGF-beta1 with recombinant human bone morphogenic protein-7 prevents this process and prevents fibrosis.
Highlights
Our study demonstrates that Epithelial to mesenchymal transition (EMT) contributes to intestinal fibrosis associated with the trinitrobenzene sulfonic acid (TNBS)-induced model of Crohn colitis and that inhibition of transforming growth factor- (TGF-)1 with recombinant human bone morphogenic protein-7 prevents this process and prevents fibrosis
Treatment with TNBS but not the vehicle control alone (45% ethanol) was associated with colitis marked by considerable thickening of the submucosa, infiltration by immune cells, and destruction of the epithelial layers on hematoxylin and eosin (H&E) (Fig. 1, A and B)
B, fibrotic colonic tissue samples from mice treated with TNBS demonstrate increased FSP1ϩ fibroblasts and colocalization of fibroblastspecific protein 1 (FSP1) and -gal, indicating EMT
Summary
Supported by National Institutes of Health Grant T32DK07760. Supported by National Institutes of Health Grants 5K08DK074558 and R03DK081687 and by a grant from the Harvard Digestive Diseases Center Pilot and Feasibility Awards Program. Chronic inflammation combined with dysregulated wound healing is thought to result in a number of complications including fistula and fibrostenotic stricture formation [3, 4]. Epithelial to mesenchymal transition (EMT) is a key contributor to the pool of activated fibroblasts in multiple organ systems including the heart, lung, liver, and kidney [13,14,15,16,17]. BMP-7 was first recognized for its regulatory effect on bone and cartilage formation and is currently employed clinically to accelerate fracture heal-
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