ACTIVATED INTESTINAL MUSCLE CELLS PROMOTE PREADIPOCYTE MIGRATION: A NOVEL MECHANISM OF CREEPING FAT FORMATION IN CROHN'S DISEASE. (21st January 2021)

• Record Type: Journal Article
• Authors: Mao, Ren; Doyon, Genevieve; Gordon, Ilyssa; Li, Jiannan; Lin, Sinan; Wang, Jie; Le, Thi Hong Nga; Elias, Michael; Kurada, Satya; Southern, Brian; Olman, Mitchell; Zhao, Shuai; Dejanovic, Dina; Chandra, Jyotsna; Pranab, Mukherjee; West, Gail; van Wagoner, David; Fiocchi, Claudio; Rieder, Florian
• Is Part Of: Inflammatory bowel diseases. Volume 27(2021)Supplement 1
• Page Start: S34
• Page End: S34
• Publication Date: 2021-01-21
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izaa347.082
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Background and Aims: Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn's disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems. Methods: Tissues from normal, ulcerative colitis, non-strictured and strictured Crohn's disease intestinal specimens were obtained. Fresh and decellularized tissue, mesenteric fat explants, primary human adipocytes, pre-adipocytes, muscularis propria cells, and native extracellular matrix were used in multiple ex vivo and in vitro systems involving cell growth, differentiation and migration, proteomics, and integrin expression. Results: Crohn's disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by TGF-b1. The muscle cell-derived matrix triggered migration of pre-adipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the pre-adipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularized intestinal tissue extracellular matrix. Conclusion: Crohn's disease creeping fat appears to result from the migration of pre-adipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.