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

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Authors: Coombes, J. D.; Swiderska-Syn, M.; Dolle, L.; Reid, D.; Eksteen, B.; Claridge, L.; Briones-Orta, M. A.; Shetty, S.; Oo, Y. H.; Riva, A.; Chokshi, S.; Papa, S.; Mi, Z.; Kuo, P. C.; Williams, R.; Canbay, A.; Adams, D. H.; Diehl, A. M.; van Grunsven, L. A.; Choi, S. S.; Syn, W. K.
Article 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)-beta, 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-beta 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.
Journal Title: Gut
Volume: 64
Issue: 7
ISSN: 1468-3288; 0017-5749
Publisher: Unknown  
Date Published: 2015
Start Page: 1120
End Page: 1131
Language: ENG
DOI/URL:

10.1136/gutjnl-2013-306484
Notes: LR: 20150708; CI: 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.archer.luhs.org/group/rights-licensing/permissions.; GR: 5K08DK080980/DK/NIDDK NIH HHS/United States; GR: K08 DK080980/DK/NIDDK NIH HHS/United States; GR: R01 DK077794/DK/NIDDK NIH HHS/United States; GR: R01 DK077794/DK/NIDDK NIH HHS/United States; JID: 2985108R; 0 (SOX9 Transcription Factor); 0 (Sox9 protein, mouse); 0 (Transforming Growth Factor beta); 106441-73-0 (Osteopontin); NIHMS702937; OID: NLM: NIHMS702937 [Available on 07/01/16]; OID: NLM: PMC4487727 [Available on 07/01/16]; PMCR: 2016/07/01 00:00; 2013/11/25 [received]; 2014/05/22 [accepted]; 2014/06/05 [aheadofprint]; ppublish