Inflammation-Induced Endothelial-to-Mesenchymal Transition: A Novel Mechanism of Intestinal Fibrosis

• Published in: The American journal of pathology Vol. 179; no. 5; pp. 2660 - 2673
• Main Authors: RIEDER, Florian, KESSLER, Sean P, WEST, Gail A, BHILOCHA, Shardul, DE LA MOTTE, Carol, SADLER, Tammy M, GOPALAN, Banu, STYLIANOU, Eleni, FIOCCHI, Claudio
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Investigative Pathology 01.11.2011
• Subjects: Animals; Biological and medical sciences; Cell Movement - physiology; Cell Transdifferentiation - genetics; Cell Transdifferentiation - physiology; Cells, Cultured; Colitis - pathology; Collagen Type I - metabolism; Cytokines - metabolism; Down-Regulation; Endothelial Cells - pathology; Endothelium, Vascular - pathology; Extracellular Matrix - secretion; Female; Fibrosis; Humans; Inflammatory Bowel Diseases - pathology; Investigative techniques, diagnostic techniques (general aspects); Lipoproteins, LDL - metabolism; Male; Medical sciences; Mesoderm - pathology; Mice; Mice, Inbred Strains; Microvessels - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Regular; Transcription Factors - metabolism; Up-Regulation; Anatomic pathology; Endothelial cell; Digestive system; Fibrosis; Gut; Mesenchyma; Inflammation; Mesenchymal cell; Mechanism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2011.07.042

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.