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

Publication ,  Journal Article
Coombes, JD; Swiderska-Syn, M; Dollé, L; Reid, D; Eksteen, B; Claridge, L; Briones-Orta, MA; Shetty, S; Oo, YH; Riva, A; Chokshi, S; Papa, S ...
Published in: Gut
July 2015

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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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

July 2015

Volume

64

Issue

7

Start / End Page

1120 / 1131

Location

England

Related Subject Headings

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

Citation

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Coombes, J. D., Swiderska-Syn, M., Dollé, L., Reid, D., Eksteen, B., Claridge, L., … Syn, W. K. (2015). Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut, 64(7), 1120–1131. https://doi.org/10.1136/gutjnl-2013-306484
Coombes, J. D., M. Swiderska-Syn, L. Dollé, D. Reid, B. Eksteen, L. Claridge, M. A. Briones-Orta, et al. “Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.Gut 64, no. 7 (July 2015): 1120–31. https://doi.org/10.1136/gutjnl-2013-306484.
Coombes JD, Swiderska-Syn M, Dollé L, Reid D, Eksteen B, Claridge L, et al. Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut. 2015 Jul;64(7):1120–31.
Coombes, J. D., et al. “Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.Gut, vol. 64, no. 7, July 2015, pp. 1120–31. Pubmed, doi:10.1136/gutjnl-2013-306484.
Coombes JD, Swiderska-Syn M, Dollé L, Reid D, Eksteen B, Claridge L, Briones-Orta MA, Shetty S, Oo YH, Riva A, Chokshi S, Papa S, Mi Z, Kuo PC, Williams R, Canbay A, Adams DH, Diehl AM, van Grunsven LA, Choi SS, Syn WK. Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut. 2015 Jul;64(7):1120–1131.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

July 2015

Volume

64

Issue

7

Start / End Page

1120 / 1131

Location

England

Related Subject Headings

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