Devhare Pradip B, Sasaki Reina, Shrivastava Shubham, Di Bisceglie Adrian M, Ray Ranjit, Ray Ratna B
Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA.
Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.
J Virol. 2017 Feb 28;91(6). doi: 10.1128/JVI.02225-16. Print 2017 Mar 15.
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. 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 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.
肝脏中的纤维化途径主要由肝星状细胞（HSC）的激活来调节。纤维化与慢性丙型肝炎病毒（HCV）感染有关，但其机制尚不清楚。HSC是肝脏中非实质细胞的主要组成部分。由于HCV不在HSC中复制，我们推测HCV感染的肝细胞分泌的外泌体可激活HSC。将原代或永生化的人肝星状（LX2）细胞暴露于来自HCV感染肝细胞的外泌体（HCV-exo）中，并检测纤维化相关基因的表达。我们的结果表明，HCV-exo被HSC内化并增加了促纤维化标志物的表达。进一步分析表明，HCV-exo携带miR-19a并靶向HSC中的SOCS3，进而激活STAT3介导的转化生长因子β（TGF-β）信号通路并增强纤维化标志物基因。与健康志愿者和非HCV相关肝病纤维化患者相比，在HCV感染的肝细胞和慢性HCV纤维化患者的血清中也观察到外泌体中miR-19a的表达较高。总之，我们的结果表明，HCV感染肝细胞来源的外泌体携带的miR-19a通过调节SOCS-STAT3轴激活HSC。我们的结果暗示了外泌体介导的细胞间通讯在HCV感染中肝纤维化HSC激活中的新机制。HCV相关的肝纤维化是终末期肝病进展的关键步骤。然而，HCV感染的肝细胞激活肝星状细胞的分子机制尚未得到充分研究。在这里，我们揭示了外泌体携带的miR-19a在HCV感染的肝细胞与HSC之间的细胞间通讯中在促纤维化激活中的作用。此外，我们证明了外泌体miR-19a在HSC中STAT3-TGF-β通路激活中的作用。这项研究有助于理解HCV感染期间肝病发病机制中的细胞间通讯。
