{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:11:43Z","timestamp":1789776703245,"version":"4.0.1"},"reference-count":54,"publisher":"Wiley","license":[{"start":{"date-parts":[[2018,12,24]],"date-time":"2018-12-24T00:00:00Z","timestamp":1545609600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Stem Cells International"],"published-print":{"date-parts":[[2018,12,24]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>. There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. <jats:italic>Methods<\/jats:italic>. NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2\u2009mL\/kg 50% carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15\u2009<jats:italic>\u03bc<\/jats:italic>g\/kg) and at week 3 in rats with liver fibrosis (20\u2009<jats:italic>\u03bc<\/jats:italic>g\/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated <jats:italic>in vitro<\/jats:italic>. <jats:italic>Results<\/jats:italic>. AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (<jats:italic>Tnf-<\/jats:italic>) <jats:italic>\u03b1<\/jats:italic>, interleukin- (<jats:italic>Il-<\/jats:italic>) <jats:italic>1\u03b2<\/jats:italic> and <jats:italic>Il-6<\/jats:italic>, and transforming growth factor- (<jats:italic>Tgf-<\/jats:italic>) <jats:italic>\u03b2<\/jats:italic>. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. <jats:italic>In vitro<\/jats:italic>, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)\/toll-like receptor 4 (TLR4) signaling pathway. <jats:italic>Conclusions<\/jats:italic>. AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.<\/jats:p>","DOI":"10.1155\/2018\/3212643","type":"journal-article","created":{"date-parts":[[2018,12,24]],"date-time":"2018-12-24T18:31:41Z","timestamp":1545676301000},"page":"1-15","source":"Crossref","is-referenced-by-count":135,"title":["Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats"],"prefix":"10.1155","volume":"2018","author":[{"given":"Masatsugu","family":"Ohara","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1194-4149","authenticated-orcid":true,"given":"Shunsuke","family":"Ohnishi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University 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