J D Coombes1, M Swiderska-Syn2, L Dollé3, D Reid4, B Eksteen4, L Claridge5, M A Briones-Orta1, S Shetty5, Y H Oo5, A Riva6, S Chokshi6, S Papa7, Z Mi8, P C Kuo8, R Williams1, A Canbay9, D H Adams5, A M Diehl2, L A van Grunsven3, S S Choi10, W K Syn11. 1. Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK. 2. Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA. 3. Faculty of Medicine and Pharmacy, Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Vrije Universiteit Brussel, Brussels, Belgium. 4. Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, Calgary, Canada. 5. Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK. 6. Viral Hepatitis Group, The Institute of Hepatology, Foundation for Liver Research, London, UK. 7. Cell Signaling Group, The Institute of Hepatology, Foundation for Liver Research, London, UK. 8. Department of Surgery, Loyola University, Chicago, USA. 9. Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany. 10. Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA Section of Gastroenterology, Department of Medicine, Durham Veteran Affairs Medical Center, Durham, North Carolina, USA. 11. Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK Department of Hepatology, Barts Health NHS Trust, London, 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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