{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T05:18:34Z","timestamp":1773724714161,"version":"3.50.1"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T00:00:00Z","timestamp":1555027200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane\u2010bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell\u2013derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)<jats:sup>\u2010\/\u2010<\/jats:sup> mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV\u2010treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal\u20107 (let\u20107). Further evaluation of let\u20107 in MDR2<jats:sup>\u2010\/\u2010<\/jats:sup> mice and human primary sclerosing cholangitis samples showed reduced levels of let\u20107 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let\u20107 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL\u201013 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF\u2010\u03baB (nuclear factor kappa B), are elevated in MDR2<jats:sup>\u2010\/\u2010 <\/jats:sup>mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF\u2010\u03baB and IL\u201013 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV\u2010treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.<\/jats:p>","DOI":"10.1002\/hep.30542","type":"journal-article","created":{"date-parts":[[2019,2,6]],"date-time":"2019-02-06T01:25:01Z","timestamp":1549416301000},"page":"2562-2578","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal\u20107 microRNA"],"prefix":"10.1097","volume":"69","author":[{"given":"Kelly","family":"McDaniel","sequence":"first","affiliation":[{"name":"Research Department,Central Texas Veterans Health Care 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University,Guangzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisaku","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University Health Science Center College of Medicine,Temple,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Venter","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University Health Science Center College of Medicine,Temple,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovica","family":"Ceci","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology,Texas A&M University Health Science Center College of Medicine,Temple,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Demeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery and Center for Translational Medicine,the First Affiliated 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