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Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti\u2010fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010 or thioacetic acid\u2010induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl<jats:sub>4<\/jats:sub>\u2010treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST\/ALT levels and hepatic or circulating pro\u2010inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26\u2010labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury\u2010induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl<jats:sub>4<\/jats:sub>. <jats:italic>In vitro<\/jats:italic>, EVN decreased proliferation and fibrosis\u2010associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl<jats:sub>4<\/jats:sub> or ethanol on hepatocyte proliferation. In mice, microRNA\u201034c, \u2010151\u20103p, \u2010483\u20105p, \u2010532\u20105p and \u2010687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and\/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX\u20102 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR\u201034c, \u2010151\u20103p, \u2010483\u20105p or \u2010532\u20105p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti\u2010fibrogenic and anti\u2010fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes.<\/jats:p><jats:p><jats:bold>Abbreviations:<\/jats:bold> ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl<jats:sub>4<\/jats:sub>: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP\u20101: monocyte chemotactic protein\u20101; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT\u2010PCR: quantitative real\u2010time polymerase chain reaction; SDS\u2010PAGE: sodium dodecyl sulphate \u2013 polyacrylamide gel electrophoresis; \u03b1SMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF\u2010\u03b2: transforming growth factor beta; TEM: transmission electron microscopy; TNF\u03b1: tumour necrosis factor alpha.<\/jats:p>","DOI":"10.1080\/20013078.2018.1461505","type":"journal-article","created":{"date-parts":[[2018,4,17]],"date-time":"2018-04-17T05:41:07Z","timestamp":1523943667000},"update-policy":"https:\/\/doi.org\/10.1080\/tandf_crossmark_01","source":"Crossref","is-referenced-by-count":103,"title":["Therapeutic effects of serum extracellular vesicles in liver fibrosis"],"prefix":"10.1002","volume":"7","author":[{"given":"Li","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Research The Research Institute at Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruju","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research The 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