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Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice
  1. J D Coombes1,
  2. M Swiderska-Syn2,
  3. L Dollé3,
  4. D Reid4,
  5. B Eksteen4,
  6. L Claridge5,
  7. M A Briones-Orta1,
  8. S Shetty5,
  9. Y H Oo5,
  10. A Riva6,
  11. S Chokshi6,
  12. S Papa7,
  13. Z Mi8,
  14. P C Kuo8,
  15. R Williams1,
  16. A Canbay9,
  17. D H Adams5,
  18. A M Diehl2,
  19. L A van Grunsven3,
  20. S S Choi2,10,
  21. W K Syn1,5,11
  1. 1Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK
  2. 2Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA
  3. 3Faculty of Medicine and Pharmacy, Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Vrije Universiteit Brussel, Brussels, Belgium
  4. 4Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, Calgary, Canada
  5. 5Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK
  6. 6Viral Hepatitis Group, The Institute of Hepatology, Foundation for Liver Research, London, UK
  7. 7Cell Signaling Group, The Institute of Hepatology, Foundation for Liver Research, London, UK
  8. 8Department of Surgery, Loyola University, Chicago, USA
  9. 9Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany
  10. 10Section of Gastroenterology, Department of Medicine, Durham Veteran Affairs Medical Center, Durham, North Carolina, USA
  11. 11Department of Hepatology, Barts Health NHS Trust, London, UK
  1. Correspondence to Dr Wing-Kin Syn, The Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK; wsyn{at}doctors.org.uk

Abstract

Background Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis.

Methods Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease.

Results OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-β signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis.

Conclusions OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.

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