1. Academic Validation
  2. Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn's disease

Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn's disease

  • Gut. 2022 Jan;71(1):55-67. doi: 10.1136/gutjnl-2020-323719.
Ren Mao 1 Genevieve Doyon 2 3 Ilyssa O Gordon 4 Jiannan Li 3 Sinan Lin 3 Jie Wang 3 Thi Hong Nga Le 3 Michael Elias 3 Satya Kurada 3 Brian Southern 3 Mitchell Olman 3 Minhu Chen 1 Shuai Zhao 3 Dina Dejanovic 3 Jyotsna Chandra 3 Pranab K Mukherjee 3 Gail West 3 David R Van Wagoner 5 Claudio Fiocchi 3 6 Florian Rieder 7 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 4 Department of Pathology, Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 5 Department of Cardiovascular and Metabolic Science, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 6 Department of Gastroenterology, Hepatology and Nutrition, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
  • 7 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA riederf@ccf.org.
Abstract

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.

Keywords

Crohn's disease; extracellular matrix; fibrosis.

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