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

被引：78

作者：

Coombes, J. D. ^{[1
]}

Swiderska-Syn, M. ^{[2
]}

Dolle, L. ^{[3
]}

Reid, D. ^{[4
]}

Eksteen, B. ^{[4
]}

Claridge, L. ^{[5
]}

Briones-Orta, M. A. ^{[1
]}

Shetty, S. ^{[5
]}

Oo, Y. H. ^{[5
]}

Riva, A. ^{[6
]}

Chokshi, S. ^{[6
]}

Papa, S. ^{[7
]}

Mi, Z. ^{[8
]}

Kuo, P. C. ^{[8
]}

Williams, R. ^{[1
]}

Canbay, A. ^{[9
]}

Adams, D. H. ^{[5
]}

Diehl, A. M. ^{[2
]}

van Grunsven, L. A. ^{[3
]}

Choi, S. S. ^{[2
,10
]}

Syn, W. K. ^{[1
,5
,11
]}

机构：

[1] Fdn Liver Res, Inst Hepatol, Regenerat & Repair Grp, London WC1E 6HX, England

[2] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC USA

[3] Vrije Univ Brussel, Fac Med & Pharm, Liver Cell Biol Lab LIVR, Dept Cell Biol CYTO, Brussels, Belgium

[4] Univ Calgary, Snyder Inst Chron Dis, HRIC, Calgary, AB, Canada

[5] Univ Birmingham, NIHR Inst Biomed Res, Liver Res Ctr, Birmingham, W Midlands, England

[6] Fdn Liver Res, Inst Hepatol, Viral Hepatitis Grp, London WC1E 6HX, England

[7] Fdn Liver Res, Inst Hepatol, Cell Signaling Grp, London WC1E 6HX, England

[8] Loyola Univ, Dept Surg, Chicago, IL 60611 USA

[9] Essen Univ Hosp, Dept Gastroenterol & Hepatol, Essen, Germany

[10] Durham Vet Affairs Med Ctr, Dept Med, Gastroenterol Sect, Durham, NC USA

[11] Barts Hlth NHS Trust, Dept Hepatol, London, England

来源：

GUT | 2015年 / 64卷 / 07期

基金：

加拿大自然科学与工程研究理事会;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; HEDGEHOG PATHWAY ACTIVATION; HEPATIC STELLATE CELLS; OVAL CELLS; DUCTULAR REACTION; IMMUNE REGULATION; BONE-MARROW; RNA APTAMER; FIBROSIS; HEPATOCYTES;

D O I：

10.1136/gutjnl-2013-306484

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：1120 / 1131

页数：12

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