Human hepatic stellate cells are not permissive for hepatitis C virus entry and replication

Florimond, A.; Chouteau, Philippe; Bruscella, Patrice; Seyec, Jacques Le; Mérour, Emilie; Ahnou, Nazim; Mallat, Ariane; Lotersztajn, Sophie; Pawlotsky, Jean‐Michel

doi:10.1136/gutjnl-2013-305634

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…HCV RNA in LX2 cells remained undetectable, suggesting the exosome-mediated transfer of HCV RNA (data not shown). Our result is also in agreement with earlier observations suggesting hepatic stellate cells do not support HCV infection and replication (12).…”

Section: Resultssupporting

confidence: 83%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

145

157

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Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor ␤ (TGF-␤) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCVinfected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-␤ pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. KEYWORDS hepatitis C virus, exosomes, miRNAs, liver fibrosis, hepatic stellate cells, microRNA H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus with a genome size of 9.6 kb that encodes several structural and nonstructural proteins. About 170 million people are infected with HCV worldwide. Chronic HCV infection often results in the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCVassociated liver fibrosis is a key pathological process leading to liver cirrhosis and HCC (1, 2), although the underlying mechanisms of disease progression remain unclear. Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis (3). Liver injury is characterized by a phenotypic and functional transformation of normally

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Section: Resultssupporting

confidence: 83%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

145

157

View full text Add to dashboard Cite

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“…HBV e antigen directly induces activation and proliferation of rat HSCs in vitro via the TGFβ pathway, and core and X proteins similarly activate human LX-2 cells via PDGFβ signaling [94, 95]. Although HCV cannot infect HSCs, viral core and non-structural proteins directly induce inflammatory and pro-fibrogenic pathways in HSCs [96, 97]. HCV core protein may promote EMT of infected hepatocytes through TGFβ signaling [98].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,029

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…However, the mechanism by which HCV induces liver fibrosis remains unclear. Particularly, whether HSCs are infected by HCV is a matter of controversy [Bataller et al, 2004;Florimond et al, 2015]. HCV NS5A can activate NF-kB and STAT-3 by inducing oxidative stress and that reactive oxygen intermediates are considered as stimuli induced HSC activation [Gong et al, 2001;Lee et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

NS5ATP13 Promotes Liver Fibrogenesis Via Activation of Hepatic Stellate Cells

Liu

Han

et al. 2017

J. Cell. Biochem.

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Liver fibrosis is a reversible wound-healing response to any etiology of chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrogenesis. Generally, persistent activation and proliferation of HSCs results in liver fibrosis progression, while primary mechanisms of liver fibrosis resolution are apoptosis and reversion to a quiescent phenotype of activated HSCs. NS5ATP13 (HCV NS5A-transactivated protein 13) is involved in nucleologenesis and tumorigenesis, but its role in liver fibrosis and HSC activation remains unclear. This study found that NS5ATP13 was upregulated in both fibrotic liver tissues and activated human HSCs induced by TGF-β1. Moreover, NS5ATP13 enhanced extracellular matrix (ECM) production and HSC activation, with or without TGF-β1 treatment, likely involving the TGF-β1/Smad3 signaling pathway. Additionally, NS5ATP13 boosted HSC proliferation by inhibiting cell apoptosis. Furthermore, HCV NS5A promoted the profibrogenic effect of NS5ATP13 partly through TGF-β1 and NF-κB p65 (RelA) upregulation. Meanwhile, NS5ATP13 was required for the pro-fibrogenic effect of NF-κB. Moreover, NS5ATP13 and NF-κB phosphorylation as well as HSC activation were reduced by CX-4945, a CK2 specific inhibitor. These findings indicated that NS5ATP13 acts as a profibrogenic factor, providing a potential target for antifibrotic therapies. J. Cell. Biochem. 118: 2463-2473, 2017. © 2017 Wiley Periodicals, Inc.

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Human hepatic stellate cells are not permissive for hepatitis C virus entry and replication

Cited by 19 publications

References 41 publications

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Hepatic stellate cells as key target in liver fibrosis

NS5ATP13 Promotes Liver Fibrogenesis Via Activation of Hepatic Stellate Cells

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