title: Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells.
abstract: 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 β (TGF-β) 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.IMPORTANCEHCV-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 HCV-infected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-β pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection.
authors.affiliation: Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Pradip B
authors.initials: PB
authors.lastname: Devhare
authors.affiliation: Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Reina
authors.initials: R
authors.lastname: Sasaki
authors.affiliation: Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Shubham
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.|Liver Center, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.affiliation: Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.|Liver Center, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA rayrb@slu.edu.|Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.|Liver Center, Saint Louis University, Saint Louis, Missouri, USA.
authors.forename: Ratna B
authors.initials: RB
authors.lastname: Ray
mesh_terms: D002450:Cell Communication; D002478:Cells, Cultured; D004705:Endocytosis; D055354:Exosomes / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000473:pathology*; D022781:Hepatocytes / Q000502:physiology* / Q000821:virology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: C549214:MIRN19A microRNA, human; D035683:MicroRNAs; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein
keywords: exosomes; hepatic stellate cells; hepatitis C virus; liver fibrosis; miRNAs; microRNA