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Bone marrow transplantation improves hepatic fibrosis in Abcb4−/− mice via Th1 response and matrix metalloproteinase activity
  1. Martin Roderfeld1,
  2. Timo Rath1,
  3. Sravanthi Pasupuleti1,
  4. Marc Zimmermann1,
  5. Caterina Neumann1,
  6. Yuri Churin1,
  7. Christian Dierkes2,
  8. Robert Voswinckel3,
  9. Peter J Barth2,
  10. Daniel Zahner4,
  11. Jürgen Graf5,6,
  12. Elke Roeb1
  1. 1Department of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany
  2. 2Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
  3. 3Department of Pneumology, Justus-Liebig-University Giessen, Giessen, Germany
  4. 4Division of Animal Welfare and Ethology, Institute of Veterinary Physiology, Justus Liebig University Giessen, Giessen, Germany
  5. 5Aero Medical Center, Deutsche Lufthansa AG, Frankfurt am Main, Germany
  6. 6Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
  1. Correspondence to Professor Dr Elke Roeb, Department of Gastroenterology, Justus-Liebig-University Giessen, Klinikstrasse 33, 35385 Gießen, Germany; elke.roeb{at}innere.med.uni-giessen.de

Abstract

Objective Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4−/− mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.

Methods After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4−/− mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.

Results 20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon γ was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.

Conclusion These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.

  • Liver fibrosis
  • T-cell polarisation
  • matrix metalloproteinase
  • cholangitis
  • stem cells
  • hepatic fibrosis
  • inflammatory bowel disease
  • liver cirrhosis
  • matrix
  • matrix metalloproteinase
  • IBD basic research
  • acute hepatitis
  • acute liver failure
  • cell cycle control
  • cell death
  • helicobacter pylori

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Footnotes

  • MR and TR contributed equally to this paper.

  • Funding This work was supported by grants from the Deutsche Forschungsgemeinschaft (RO 957/8-1) and by a Research Grant from the University Medical Center Giessen and Marburg (UKGM 10/2010 GI). TR received starting grants from the Justus-Liebig-University Giessen.

  • Competing interests None.

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

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