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 Choi; W K Syn

doi:10.1136/gutjnl-2013-306484

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

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

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)-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 language	English
Pages (from-to)	1120-31
Number of pages	12
Journal	Gut
Volume	64
Issue number	7
DOIs	https://doi.org/10.1136/gutjnl-2013-306484
Publication status	Published - 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.

Keywords

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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10.1136/gutjnl-2013-306484

Intrahepatic Signals Involve in the Recruitment and Differentiation of IL-17 Secreting T Cells and Regulatory T Cells in Chronic Hepatitis - Fellowship
Oo, Y.
Medical Research Council
4/01/12 → 5/01/18
Project: Research Councils

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Coombes, J. D., Swiderska-Syn, M., Dollé, 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., ... Syn, W. K. (2015). Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut, 64(7), 1120-31. https://doi.org/10.1136/gutjnl-2013-306484

@article{4265c7bd0ba04935a6b116597b4cacd3,

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)-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.",

keywords = "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",

author = "Coombes, {J D} and M Swiderska-Syn and L Doll{\'e} and D Reid and B Eksteen and L Claridge and Briones-Orta, {M A} and Shishir Shetty and Oo, {Y H} and A Riva and S Chokshi and S Papa and Z Mi and Kuo, {P C} and R Williams and A Canbay and Adams, {D H} and Diehl, {A M} and {van Grunsven}, {L A} and Choi, {S S} and Syn, {W K}",

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.",

year = "2015",

month = jul,

doi = "10.1136/gutjnl-2013-306484",

language = "English",

volume = "64",

pages = "1120--31",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "7",

}

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 2015, 'Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice', Gut, vol. 64, no. 7, pp. 1120-31. https://doi.org/10.1136/gutjnl-2013-306484

TY - JOUR

T1 - Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice

AU - Coombes, J D

AU - Swiderska-Syn, M

AU - Dollé, L

AU - Reid, D

AU - Eksteen, B

AU - Claridge, L

AU - Briones-Orta, M A

AU - Shetty, Shishir

AU - Oo, Y H

AU - Riva, A

AU - Chokshi, S

AU - Papa, S

AU - Mi, Z

AU - Kuo, P C

AU - Williams, R

AU - Canbay, A

AU - Adams, D H

AU - Diehl, A M

AU - van Grunsven, L A

AU - Choi, S S

AU - Syn, W K

N1 - 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.

PY - 2015/7

Y1 - 2015/7

N2 - 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.

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.

KW - Animals

KW - Disease Progression

KW - Down-Regulation

KW - Immunohistochemistry

KW - Liver

KW - Liver Cirrhosis

KW - Mice, Inbred C57BL

KW - Osteopontin

KW - SOX9 Transcription Factor

KW - Stem Cells

KW - Transforming Growth Factor beta

KW - Up-Regulation

KW - Wound Healing

U2 - 10.1136/gutjnl-2013-306484

DO - 10.1136/gutjnl-2013-306484

M3 - Article

C2 - 24902765

SN - 0017-5749

VL - 64

SP - 1120

EP - 1131

JO - Gut

JF - Gut

IS - 7

ER -

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

Abstract

Bibliographical note

Keywords

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Intrahepatic Signals Involve in the Recruitment and Differentiation of IL-17 Secreting T Cells and Regulatory T Cells in Chronic Hepatitis - Fellowship

Cite this