Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activation

Feng Hong, Ana Tuyama, Ting Fang Lee, Johnny C. Loke, Ritu Agarwal, Xin Cheng, Anita Garg, M. Isabel Fiel, Myron Schwartz, Jose Walewski, Andrea Branch, Alison D. Schecter, Meena B. Bansal

Research output: Contribution to journalArticle

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Abstract

Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell- derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression ofα-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α-induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.

Original languageEnglish (US)
Pages (from-to)2055-2067
Number of pages13
JournalHepatology
Volume49
Issue number6
DOIs
StatePublished - Jun 2009
Externally publishedYes

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Chemokine CXCL12
Hepatic Stellate Cells
CXCR4 Receptors
Collagen
Mitogen-Activated Protein Kinase 3
Liver
Mitogen-Activated Protein Kinase 1
Hepatitis C
Cell Proliferation
1-Phosphatidylinositol 4-Kinase
Cell Surface Receptors
Chemokines
Smooth Muscle
Actins
Fibrosis
Phosphorylation
Staining and Labeling
Ligands
Messenger RNA

ASJC Scopus subject areas

  • Hepatology

Cite this

Hepatic stellate cells express functional CXCR4 : Role in stromal cell-derived factor-1α-mediated stellate cell activation. / Hong, Feng; Tuyama, Ana; Lee, Ting Fang; Loke, Johnny C.; Agarwal, Ritu; Cheng, Xin; Garg, Anita; Fiel, M. Isabel; Schwartz, Myron; Walewski, Jose; Branch, Andrea; Schecter, Alison D.; Bansal, Meena B.

In: Hepatology, Vol. 49, No. 6, 06.2009, p. 2055-2067.

Research output: Contribution to journalArticle

Hong, F, Tuyama, A, Lee, TF, Loke, JC, Agarwal, R, Cheng, X, Garg, A, Fiel, MI, Schwartz, M, Walewski, J, Branch, A, Schecter, AD & Bansal, MB 2009, 'Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activation', Hepatology, vol. 49, no. 6, pp. 2055-2067. https://doi.org/10.1002/hep.22890
Hong, Feng ; Tuyama, Ana ; Lee, Ting Fang ; Loke, Johnny C. ; Agarwal, Ritu ; Cheng, Xin ; Garg, Anita ; Fiel, M. Isabel ; Schwartz, Myron ; Walewski, Jose ; Branch, Andrea ; Schecter, Alison D. ; Bansal, Meena B. / Hepatic stellate cells express functional CXCR4 : Role in stromal cell-derived factor-1α-mediated stellate cell activation. In: Hepatology. 2009 ; Vol. 49, No. 6. pp. 2055-2067.
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abstract = "Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell- derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression ofα-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α-induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.",
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T2 - Role in stromal cell-derived factor-1α-mediated stellate cell activation

AU - Hong, Feng

AU - Tuyama, Ana

AU - Lee, Ting Fang

AU - Loke, Johnny C.

AU - Agarwal, Ritu

AU - Cheng, Xin

AU - Garg, Anita

AU - Fiel, M. Isabel

AU - Schwartz, Myron

AU - Walewski, Jose

AU - Branch, Andrea

AU - Schecter, Alison D.

AU - Bansal, Meena B.

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N2 - Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell- derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression ofα-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α-induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.

AB - Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell- derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression ofα-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α-induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.

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