Exosomal MALAT1 Derived From Hepatic Cells Is Involved in the Activation of Hepatic Stellate Cells via miRNA-26b in Fibrosis Induced by Arsenite

In the liver microenvironment, interactions among diverse types of hepatic cells are involved in liver fibrosis. In fibrotic tissues, exosomes act as transporters in intercellular communication. Long non-coding RNAs (lncRNAs) are involved in the activation of hepatic stellate cells (HSCs), which are participants in liver fibrosis. However, the functions of exosomal lncRNAs in liver fibrosis induced by arsenite are undefined. The purposes of the present study were (a) to determine if lncRNAs secreted from human hepatic (L-02) cells exposed to arsenite are shuttled to hepatic stellate LX-2 cells and (b) to establish their effects on LX-2 cells. In mice, MALAT1 was overexpressed in the progression of liver fibrosis induced by arsenite as well as in L-02 cells exposed to arsenite. Co-cultures with arsenite-treated L-02 cells induced the activation of LX-2 cells and overexpression of MALAT1. Arsenite-treated L-02 cells transported MALAT1 into LX-2 cells. Downregulation of MALAT1, which reduced the MALAT1 levels in exosomes derived from arsenite-treated L-02 cells, inhibited the activation of LX-2 cells. Additionally, exosomal MALAT1 derived from arsenite-treated L-02 cells promoted the activation of LX-2 cells via microRNA-26b regulation of COL1A2. Furthermore, circulating exosomal MALAT1 was up-regulated in people exposed to arsenite. In sum, exosomes derived from arsenite-treated hepatic cells transferred MALAT1 to HSCs, which induced their activation. These findings support the concept that, during liver fibrosis induced by arsenite, exosomal lncRNAs are involved in cell-cell communication. Funding Statement: This work was supported by the Natural Science Foundations of China (81730089, 81430077); the National Key Research and Development Program of China (2016YFE0204900); the open project of Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment and Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, China (JX21817902/009); the open project of the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, China (GMU-2018-HJZ01); and the Priority Academic Program Development of Jiangsu Higher Education Institutions (2018). Declaration of Interests: The authors declare they have no competing financial interests. Ethics Approval Statement: Animals were treated humanely and with regard for alleviation of suffering according to a protocol approved by the Institutional Animal Care and Use committee (IACUC) of Nanjing Medical University.