Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice

J D Coombes, M Swiderska-Syn, L Dollé, D Reid, B Eksteen, L Claridge, M A Briones-Orta, Shishir Shetty, Y H Oo, A Riva, S Chokshi, S Papa, Z Mi, P C Kuo, R Williams, A Canbay, D H Adams, A M Diehl, L A van Grunsven, S S ChoiW K Syn

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53 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1120-31
Number of pages12
Issue number7
Publication statusPublished - Jul 2015

Bibliographical note

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.


  • Animals
  • Disease Progression
  • Down-Regulation
  • Immunohistochemistry
  • Liver
  • Liver Cirrhosis
  • Mice, Inbred C57BL
  • Osteopontin
  • SOX9 Transcription Factor
  • Stem Cells
  • Transforming Growth Factor beta
  • Up-Regulation
  • Wound Healing


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