Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis
| Autor: | Florian, Rieder, Sean P, Kessler, Gail A, West, Shardul, Bhilocha, Carol, de la Motte, Tammy M, Sadler, Banu, Gopalan, Eleni, Stylianou, Claudio, Fiocchi |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Down-Regulation Endothelial Cells Mice Inbred Strains Regular Article Colitis Inflammatory Bowel Diseases Fibrosis Collagen Type I Extracellular Matrix Up-Regulation Lipoproteins LDL Mesoderm Mice Phenotype Cell Movement Cell Transdifferentiation Microvessels Animals Cytokines Humans Female Endothelium Vascular Cells Cultured Transcription Factors |
| Zdroj: | The American journal of pathology. 179(5) |
| ISSN: | 1525-2191 |
| Popis: | In addition to mesenchymal cells, endothelial cells may contribute to fibrosis through the process of endothelial-to-mesenchymal transition (EndoMT). We investigated whether human intestinal microvascular endothelial cells (HIMEC) undergo EndoMT and contribute to fibrosis in human and experimental inflammatory bowel disease (IBD). HIMEC were exposed to TGF-β1, IL-1β, and TNF-α or supernatants of lamina propria mononuclear cells (LPMC) and evaluated for morphological, phenotypic, and functional changes compatible with EndoMT. Genomic analysis was used to identify transcription factors involved in the transformation process. Evidence of in situ and in vivo EndoMT was sought in inflamed human and murine intestine. The combination of TGF-β1, IL-1β and TNF-α, or activated LPMC supernatants induced morphological and phenotypic changes consistent with EndoMT with a dominant effect by IL-1. These changes persisted after removal of the inducing agents and were accompanied by functional loss of acetylated LDL-uptake and migratory capacity, and acquisition of de novo collagen synthesis capacity. Sp1 appeared to be the main transcriptional regulator of EndoMT. EndoMT was detected in microvessels of inflammatory bowel disease (IBD) mucosa and experimental colonic fibrosis of Tie2–green fluorescent protein (GFP) reporter–expressing mice. In conclusion, chronic inflammation induces transdifferentiation of intestinal mucosal microvascular cells into mesenchymal cells, suggesting that the intestinal microvasculature contributes to IBD-associated fibrosis through the novel process of EndoMT. |
| Databáze: | OpenAIRE |
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