RT Journal Article
SR Electronic
T1 Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1120
OP 1131
DO 10.1136/gutjnl-2013-306484
VO 64
IS 7
A1 Coombes, J D
A1 Swiderska-Syn, M
A1 Dollé, L
A1 Reid, D
A1 Eksteen, B
A1 Claridge, L
A1 Briones-Orta, M A
A1 Shetty, S
A1 Oo, Y H
A1 Riva, A
A1 Chokshi, S
A1 Papa, S
A1 Mi, Z
A1 Kuo, P C
A1 Williams, R
A1 Canbay, A
A1 Adams, D H
A1 Diehl, A M
A1 van Grunsven, L A
A1 Choi, S S
A1 Syn, W K
YR 2015
UL http://gut.bmj.com/content/64/7/1120.abstract
AB 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.