Objective 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.
Design Tissues from normal, UC, non-strictured and strictured Crohn’s disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals.
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 transforming growth factor-β1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix.
Conclusion Crohn’s disease creeping fat appears to result from the migration of preadipocytes 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.
- Crohn's disease
- extracellular matrix
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Contributors Study design: RM, CF and FR. Execution/data collection: RM, GD, IOG, JL, SL, JW, TL, ME, SK, SZ, DD, JC and GW. Data compilation and analysis: RM, GD, IOG, JL, SL, JW, THNL, ME, SK, SZ, DD, JC and GW. Oversight/advisory: RM, BS, MO, PKM, DRVW, CF and FR. Wrote and edited manuscript: RM, MC, CF and FR. Acquired funding, regulatory approvals: MC and FR.
Funding This work was supported by the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium (No. 3081 to FR), the Crohn’s and Colitis Foundation (No. 569125 to FR), the National Institute of Health (NIDDK K08DK110415 and R01DK123233 to FR), the Cleveland Clinic through the LabCo program to FR, the Scholtz Family Foundation to FR and the National Science Foundation of China (No. 81970483 to RM).
Competing interests FR is consultant to Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, UCB and receives funding from the Crohn’s and Colitis Foundation of America, the Helmsley Charitable Trust, Kenneth Rainin Foundation and the National Institute of Health. CF received speaker fees from UCB, Genentech, Sandoz, Janssen and he is consultant for Athos Therapeutics.
Patient consent for publication Not required.
Ethics approval Cleveland Clinic IRB 17-1167.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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