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Original research
Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis
  1. Sinan Lin1,2,
  2. Jie Wang2,3,
  3. Pranab K Mukherjee2,
  4. Ren Mao1,2,
  5. Gail West2,
  6. Doug Czarnecki2,
  7. Shuai Zhao2,
  8. Quang Tam Nguyen2,
  9. Michael Elias2,
  10. William J Massey2,
  11. WeiWei Liu2,
  12. Yan Wang2,
  13. Ankita Prasad2,
  14. Suhanti Banerjee2,
  15. Idan Goren2,
  16. Jyotsna Chandra2,
  17. Hongnga T Le2,
  18. Dina Dejanovic2,
  19. Jiannan Li2,
  20. Minhu Chen1,
  21. Stefan Holubar4,
  22. Mitchell Olman2,
  23. Brian Southern2,
  24. Shaomin Hu5,
  25. Ilyssa O Gordon5,
  26. Kamran Atabai6,
  27. Claudio Fiocchi2,7,
  28. Florian Rieder2,7,8
  1. 1 Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  2. 2 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
  3. 3 Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan Province, China
  4. 4 Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
  5. 5 Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
  6. 6 Cardiovascular Research Institute, Lung Biology Center, Department of Medicine, University of California San Francisco, San Francisco, California, USA
  7. 7 Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
  8. 8 Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic, Cleveland, Ohio, USA
  1. Correspondence to Dr Florian Rieder, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, USA; riederf{at}ccf.org

Abstract

Objective Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn’s disease (CD) and control tissues.

Design Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models.

Results We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvβ5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo.

Conclusion MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.

  • CROHN'S DISEASE
  • EXTRACELLULAR MATRIX
  • FIBROGENESIS
  • FIBROSIS

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • SL and JW contributed equally.

  • Correction notice This article has been corrected since it published Online First. The author, Dr Atabai, name has been corrected.

  • Contributors Study design: SL, JW, CF, FR. Execution/data collection: SL, JW, GW, WJM, AP, WL, YW, SB, IG, DC, JC, IOG, SH. Data compilation and analysis: SL, JW, QTN, HTL, PM. Oversight/advisory: SL, JW, PKM, SH, RM, GW, DC, JL, QTN, SZ, ME, HL, DD, MC, MO, HTL, BS, KA, CF, CR. Wrote and edited manuscript: all authors. Acquired funding, regulatory approvals: CF, FR. Guarantor: FR.

  • Funding This work was supported by the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium (No. 3081 and No. 2210-05567 to FR), the Crohn’s and Colitis Foundation (No. 569125 to FR), the National Institute of Health (NIDDK R01DK123233 & R01DK132038 to FR), the National Institutes of Health (NIDDK 2 P30 DK097948 to CF and FR), the National Science Foundation of China (81970483, 82170537 and 82222010 to RM and 82200573 to SL) and the Bureau of Science and Technology of Guangzhou (No. 2023A04J2171).

  • Competing interests The Cleveland Clinic receives funds on her behalf from Celgene, Morphic, Pfizer, UCB, GB004 and Helmsley. SDH was consultant to Shionogi, Takeda and Guidepoint and receives research funding from the Crohn’s and Colitis Foundation and the American Society of Colon and Rectal Surgeons. CF receives speaker fees from UCB, Genentech, Sandoz and Janssen, and he is the consultant of Athos Therapeutics, Inc. FR is the consultant of Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jansen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, UCB and 89Bio.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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