title: Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis.
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.
authors.affiliation: Division of Matrix Biology, Dept. of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Center for Life Science, 3 Blackfan Circle, Rm. 11090, Boston, MA 02215, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Flier
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.forename: Efi G
authors.initials: EG
authors.lastname: Kokkotou
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D007763:Lac Operon / Q000235:genetics; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011506:Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C525947:exocrine-gland-secreting peptide 1, mouse; D014302:Trinitrobenzenesulfonic Acid; D001616:beta-Galactosidase