{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:59:44Z","timestamp":1790265584818,"version":"4.1.0"},"reference-count":95,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK054811, DK076898, DK107310, DK110035, DK062975, AA025997, DK108959, AA025208, DK107682, AA026917, AA026903, AA025157, and AA026385"],"award-info":[{"award-number":["DK054811, DK076898, DK107310, DK110035, DK062975, AA025997, DK108959, AA025208, DK107682, AA026917, AA026903, AA025157, and AA026385"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"VA Merit Award","award":["5I01BX000574, 1I01BX003031, 1I01BX001724, I01CX000361"],"award-info":[{"award-number":["5I01BX000574, 1I01BX003031, 1I01BX001724, I01CX000361"]}]},{"DOI":"10.13039\/100008538","name":"PSC Partners Seeking a Cure","doi-asserted-by":"publisher","award":["TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS USING EXTRACELLULAR VESICLES"],"award-info":[{"award-number":["TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS USING EXTRACELLULAR VESICLES"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver diseases are perpetuated by the orchestration of hepatocytes and other hepatic non-parenchymal cells. These cells communicate and regulate with each other by secreting mediators such as peptides, hormones, and cytokines. Extracellular vesicles (EVs), small particles secreted from cells, contain proteins, DNAs, and RNAs as cargos. EVs have attracted recent research interests since they can communicate information from donor cells to recipient cells thereby regulating physiological events via delivering of specific cargo mediators. Previous studies have demonstrated that liver cells secrete elevated numbers of EVs during diseased conditions, and those EVs are internalized into other liver cells inducing disease-related reactions such as inflammation, angiogenesis, and fibrogenesis. Reactions in recipient cells are caused by proteins and RNAs carried in disease-derived EVs. This review summarizes cell-to-cell communication especially via EVs in the pathogenesis of liver diseases and their potential as a novel therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms20092180","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T03:15:46Z","timestamp":1557198946000},"page":"2180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Intercellular Communication between Hepatic Cells in Liver Diseases"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5380-8001","authenticated-orcid":false,"given":"Keisaku","family":"Sato","sequence":"first","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suthat","family":"Liangpunsakul","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen","family":"Kusumanchi","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Yang","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Texas A&amp;M University, Temple, TX 76504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Liver Research, Division of Gastroenterology &amp; Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.devcel.2010.01.011","article-title":"Organogenesis and development of the liver","volume":"18","author":"Lemaigre","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1016\/j.ajpath.2016.06.003","article-title":"Pathogenesis of kupffer cells in cholestatic liver injury","volume":"186","author":"Sato","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_3","first-page":"100","article-title":"Macrophages in nonalcoholic steatohepatitis: Friend or foe?","volume":"6","author":"Grunhut","year":"2018","journal-title":"Eur. Med. J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1053\/hupa.2000.8440","article-title":"Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver","volume":"31","author":"Washington","year":"2000","journal-title":"Hum. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1053\/j.gastro.2014.06.043","article-title":"Roles for chemokines in liver disease","volume":"147","author":"Marra","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/cmi.2015.104","article-title":"Hepatic macrophages in homeostasis and liver diseases: From pathogenesis to novel therapeutic strategies","volume":"13","author":"Ju","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1002\/hep.28814","article-title":"Extracellular vesicles in liver pathobiology: Small particles with big impact","volume":"64","author":"Hirsova","year":"2016","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jhep.2016.03.004","article-title":"Exosomes in liver pathology","volume":"65","author":"Sato","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nrgastro.2014.7","article-title":"The emerging roles of microvesicles in liver diseases","volume":"11","author":"Lemoinne","year":"2014","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.jhep.2013.03.028","article-title":"Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases","volume":"59","author":"Masyuk","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nri.2017.11","article-title":"Liver macrophages in tissue homeostasis and disease","volume":"17","author":"Krenkel","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","article-title":"The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"16","author":"Kazankov","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1002\/hep.510300522","article-title":"Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line","volume":"30","author":"Park","year":"1999","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.jhep.2014.10.033","article-title":"Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6\/STAT3 signalling","volume":"62","author":"Xiao","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1146\/annurev-physiol-022516-034356","article-title":"Mechanisms of organ injury and repair by macrophages","volume":"79","author":"Vannella","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9042851","DOI":"10.1155\/2017\/9042851","article-title":"Phagocytosis: A fundamental process in immunity","volume":"2017","author":"Rosales","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, X., Lei, Y., Wu, M., and Li, N. (2018). Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102958"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Liu, J., Fan, L., Yu, H., Zhang, J., He, Y., Feng, D., Wang, F., Li, X., Liu, Q., and Li, Y. (2019). Endoplasmic reticulum stress promotes liver cancer cells to release exosomal miR-23a-3p and up-regulate PD-L1 expression in macrophages. Hepatology.","DOI":"10.1002\/hep.30607"},{"key":"ref_20","first-page":"251","article-title":"Macrophages and alcohol-related liver inflammation","volume":"37","author":"Ju","year":"2015","journal-title":"Alcohol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","article-title":"Alcoholic liver disease","volume":"4","author":"Seitz","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.jhep.2015.11.020","article-title":"Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles","volume":"64","author":"Verma","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1074\/jbc.M115.694133","article-title":"MicroRNA cargo of extracellular vesicles from alcohol-exposed monocytes signals naive monocytes to differentiate into M2 macrophages","volume":"291","author":"Saha","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1002\/hep.29732","article-title":"Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90","volume":"67","author":"Saha","year":"2018","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00441-017-2753-2","article-title":"Partners in crime: Neutrophils and monocytes\/macrophages in inflammation and disease","volume":"371","author":"Nicholls","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/rb\/rbw041","article-title":"An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration","volume":"4","author":"Selders","year":"2017","journal-title":"Regen. Biomater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e92634","DOI":"10.1172\/jci.insight.92634","article-title":"Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity","volume":"2","author":"Cai","year":"2017","journal-title":"JCI Insight"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1053\/j.gastro.2015.12.037","article-title":"Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes","volume":"150","author":"Hirsova","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1002\/hep.28252","article-title":"Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes","volume":"63","author":"Ibrahim","year":"2016","journal-title":"Hepatology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1194\/jlr.M063412","article-title":"Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1alpha-dependent manner","volume":"57","author":"Kakazu","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cho, Y.E., Im, E.J., Moon, P.G., Mezey, E., Song, B.J., and Baek, M.C. (2017). Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172463"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/hep4.1210","article-title":"Abundance of cytochromes in hepatic extracellular vesicles is altered by drugs related with drug-induced liver injury","volume":"2","author":"Palomo","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1093\/toxsci\/kfw047","article-title":"Subtoxic alterations in hepatocyte-derived exosomes: An early step in drug-induced liver injury?","volume":"151","author":"Holman","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1038\/srep09991","article-title":"Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS","volume":"5","author":"Bala","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.jhep.2017.06.001","article-title":"Hepatic stellate cell activation and pro-fibrogenic signals","volume":"67","author":"Gandhi","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/cphy.c120035","article-title":"Hepatic stellate cells and liver fibrosis","volume":"3","author":"Puche","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_39","first-page":"S39","article-title":"Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: A key event in hepatic fibrogenesis","volume":"54","author":"Gressner","year":"1996","journal-title":"Kidney Int. Suppl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.surg.2014.04.014","article-title":"Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver","volume":"156","author":"Charrier","year":"2014","journal-title":"Surgery"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"G491","DOI":"10.1152\/ajpgi.00140.2015","article-title":"Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: Role of exosomes in horizontal transfer of Twist1","volume":"309","author":"Chen","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.cytogfr.2004.03.006","article-title":"Regulation of PDGF and its receptors in fibrotic diseases","volume":"15","author":"Bonner","year":"2004","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/hep.29803","article-title":"Hepatic stellate cell-derived platelet-derived growth factor receptor-alpha-enriched extracellular vesicles promote liver fibrosis in mice through SHP2","volume":"68","author":"Kostallari","year":"2018","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"G89","DOI":"10.1152\/ajpgi.00333.2016","article-title":"The emerging role of mast cells in liver disease","volume":"313","author":"Jarido","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1002\/hep.29079","article-title":"BDL-induced biliary hyperplasia, hepatic injury and fibrosis are reduced in mast cell deficient Kitw-sh mice","volume":"65","author":"Hargrove","year":"2017","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"E10692","DOI":"10.1073\/pnas.1809938115","article-title":"Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation","volume":"115","author":"Kim","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jcmgh.2015.07.007","article-title":"Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-gamma","volume":"1","author":"Povero","year":"2015","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3710","DOI":"10.1038\/s41598-017-03389-2","article-title":"Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells","volume":"7","author":"Lee","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/hep.27376","article-title":"Liver sinusoidal endothelial cells in hepatic fibrosis","volume":"61","author":"DeLeve","year":"2015","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"30684","DOI":"10.1074\/jbc.M115.671735","article-title":"Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration","volume":"290","author":"Wang","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.humpath.2018.02.018","article-title":"Propranolol prevents liver cirrhosis by inhibiting hepatic stellate cell activation mediated by the PDGFR\/Akt pathway","volume":"76","author":"Ding","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00109-017-1605-6","article-title":"PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-beta1 signaling to PI3Kgamma\/AKT\/Rac1 pathway","volume":"96","author":"Xu","year":"2018","journal-title":"J. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.23999","article-title":"Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cells","volume":"53","author":"Kornek","year":"2011","journal-title":"Hepatology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1186\/s13046-018-0965-2","article-title":"Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts","volume":"37","author":"Zhou","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2016.07.009","article-title":"Liver sinusoidal endothelial cells: Physiology and role in liver diseases","volume":"66","author":"Poisson","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/hep.27318","article-title":"Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles","volume":"61","author":"Lemoinne","year":"2015","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"ra88","DOI":"10.1126\/scisignal.2004512","article-title":"Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells","volume":"6","author":"Povero","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1016\/j.ajpath.2018.06.015","article-title":"The secretin\/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-beta1-mediated biliary senescence","volume":"188","author":"Wu","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1242\/dev.01304","article-title":"Hedgehog signaling is essential for endothelial tube formation during vasculogenesis","volume":"131","author":"Vokes","year":"2004","journal-title":"Development"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1161\/ATVBAHA.113.302494","article-title":"Hedgehog-dependent regulation of angiogenesis and myogenesis is impaired in aged mice","volume":"33","author":"Renault","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1053\/j.gastro.2008.09.066","article-title":"Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells","volume":"136","author":"Witek","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.bbadis.2017.06.017","article-title":"Mechanisms of cholangiocyte responses to injury","volume":"1864","author":"Sato","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/hep.30150","article-title":"Ductular reaction in liver diseases: Pathological mechanisms and translational significances","volume":"69","author":"Sato","year":"2019","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1002\/hep.26993","article-title":"Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis","volume":"59","author":"Tabibian","year":"2014","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/labinvest.2014.94","article-title":"Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis","volume":"94","author":"Tabibian","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/hep.29138","article-title":"Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells","volume":"66","author":"Wan","year":"2017","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"G990","DOI":"10.1152\/ajpgi.00093.2010","article-title":"Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia","volume":"299","author":"Masyuk","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"G1013","DOI":"10.1152\/ajpgi.00383.2012","article-title":"Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling","volume":"304","author":"Masyuk","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0168-8278(98)80058-5","article-title":"Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis","volume":"29","author":"Sasatomi","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"11183","DOI":"10.1038\/s41598-017-10694-3","article-title":"The role of the secretin\/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles","volume":"7","author":"Sato","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/hep.29145","article-title":"The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice","volume":"66","author":"Li","year":"2017","journal-title":"Hepatology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1002\/hep.29838","article-title":"Cholangiocyte-derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans","volume":"68","author":"Li","year":"2018","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4197857","DOI":"10.1155\/2018\/4197857","article-title":"Current perspectives regarding stem cell-based therapy for liver cirrhosis","volume":"2018","author":"Kwak","year":"2018","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1089\/scd.2012.0395","article-title":"Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis","volume":"22","author":"Li","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.ymthe.2016.11.019","article-title":"hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury","volume":"25","author":"Yan","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"6079642","DOI":"10.1155\/2018\/6079642","article-title":"Human umbilical cord MSC-derived exosomes suppress the development of CCl4-induced liver injury through antioxidant effect","volume":"2018","author":"Jiang","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13287-019-1204-2","article-title":"Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt\/beta-catenin pathway","volume":"10","author":"Rong","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/sctm.16-0226","article-title":"Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice","volume":"6","author":"Haga","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"McDaniel, K., Wu, N., Zhou, T., Huang, L., Sato, K., Venter, J., Ceci, L., Chen, D., Ramos-Lorenzo, S., and Invernizzi, P. (2019). Amelioration of ductular reaction by stem cell derived extracellular vesicles in MDR2 knockout mice via let-7 microRNA. Hepatology.","DOI":"10.1002\/hep.30542"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1074\/jbc.M110.145870","article-title":"Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor \u03b1 (TNF\u03b1) production via increased mRNA half-life in alcoholic liver disease","volume":"286","author":"Bala","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/1479-5876-10-151","article-title":"Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection","volume":"10","author":"Bala","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/hep.29833","article-title":"Expression of microRNA-155 in inflammatory cells modulates liver injury","volume":"68","author":"Blaya","year":"2018","journal-title":"Hepatology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10721","DOI":"10.1038\/srep10721","article-title":"Biodistribution and function of extracellular miRNA-155 in mice","volume":"5","author":"Bala","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/j.nano.2014.03.014","article-title":"Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages","volume":"10","author":"Bala","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Antimisiaris, S.G., Mourtas, S., and Marazioti, A. (2018). Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. Pharmaceutics, 10.","DOI":"10.20944\/preprints201810.0507.v1"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJMra1506330","article-title":"Primary sclerosing cholangitis","volume":"375","author":"Lazaridis","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1080\/17474124.2018.1473761","article-title":"Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis","volume":"12","author":"Taghavi","year":"2018","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/hep.29291","article-title":"Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma","volume":"66","author":"Arbelaiz","year":"2017","journal-title":"Hepatology"},{"key":"ref_89","first-page":"257","article-title":"Exosomal microRNAs as potential biomarkers for cancer cell migration and prognosis in hepatocellular carcinoma patient-derived cell models","volume":"41","author":"Yu","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrgastro.2017.71","article-title":"Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets","volume":"14","author":"Szabo","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.pharmthera.2018.03.009","article-title":"Extracellular vesicles as potential biomarkers for alcohol- and drug-induced liver injury and their therapeutic applications","volume":"187","author":"Cho","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"415","DOI":"10.3389\/fphar.2018.00415","article-title":"Extracellular vesicles as carriers of non-coding RNAs in liver diseases","volume":"9","author":"Yang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"26316","DOI":"10.3402\/jev.v4.26316","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"4","author":"Wiklander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.jhep.2017.11.025","article-title":"Role of bile acids in the gut-liver axis","volume":"68","author":"Schneider","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/liv.13009","article-title":"The enteric microbiome in hepatobiliary health and disease","volume":"36","author":"Tabibian","year":"2016","journal-title":"Liver Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2180\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:48:46Z","timestamp":1760186926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,2]]},"references-count":95,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20092180"],"URL":"https:\/\/doi.org\/10.3390\/ijms20092180","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,2]]}}}