title: Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.
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.
authors.affiliation: Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Coombes
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: Faculty of Medicine and Pharmacy, Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Dollé
authors.affiliation: Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, Calgary, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Reid
authors.affiliation: Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, Calgary, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Eksteen
authors.affiliation: Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: L
authors.initials: L
authors.lastname: Claridge
authors.affiliation: Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Briones-Orta
authors.affiliation: Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Shetty
authors.affiliation: Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Y H
authors.initials: YH
authors.lastname: Oo
authors.affiliation: Viral Hepatitis Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Riva
authors.affiliation: Viral Hepatitis Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Chokshi
authors.affiliation: Cell Signaling Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Papa
authors.affiliation: Department of Surgery, Loyola University, Chicago, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Mi
authors.affiliation: Department of Surgery, Loyola University, Chicago, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.affiliation: Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Canbay
authors.affiliation: Centre for Liver Research, NIHR Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Faculty of Medicine and Pharmacy, Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: L A
authors.initials: LA
authors.lastname: van Grunsven
authors.affiliation: 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.
authors.forename: S S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: W K
authors.initials: WK
authors.lastname: Syn
mesh_terms: D000818:Animals; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D014945:Wound Healing / Q000502:physiology
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016212:Transforming Growth Factor beta; D053495:Osteopontin