{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:00:58Z","timestamp":1792548058720,"version":"4.5.0"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T00:00:00Z","timestamp":1576800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN project","award":["2006067527"],"award-info":[{"award-number":["2006067527"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1). Methods. In vivo and in vitro experiments were performed to analyze the expression of OSM and OSM-receptor (OSMR) in three murine models of non-alcoholic-fatty liver disease (NAFLD) and -steatohepatitis (NASH) and in human NASH patients as well as the action of OSM on phenotypic responses of human MFs. Results: Hepatic OSM and OSMR levels were overexpressed in three murine NASH models and in NASH patients. OSM stimulates migration in human MFs by involving early intracellular ROS generation and activation of Ras\/Erk, JNK1\/2, PI3K\/Akt as well as STAT1\/STAT3 pathways and HIF-1\u03b1. OSM-dependent migration relies on a biphasic mechanism requiring early intracellular generation of reactive oxygen species (ROS) and late HIF1-dependent expression and release of VEGF. Conclusion: OSM is overexpressed in experimental and human progressive NAFLD and can act as a profibrogenic factor by directly stimulating migration of hepatic MFs.<\/jats:p>","DOI":"10.3390\/cells9010028","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T03:23:12Z","timestamp":1577071392000},"page":"28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Oncostatin M, A Profibrogenic Mediator Overexpressed in Non-Alcoholic Fatty Liver Disease, Stimulates Migration of Hepatic Myofibroblasts"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7973-9681","authenticated-orcid":false,"given":"Beatrice","family":"Foglia","sequence":"first","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0192-8199","authenticated-orcid":false,"given":"Salvatore","family":"Sutti","sequence":"additional","affiliation":[{"name":"Department of Health Science, University of East Piedmont, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Pedicini","sequence":"additional","affiliation":[{"name":"IRCC, Istituto per la Ricerca e la Cura del Cancro, Candiolo, 10060 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9883-6882","authenticated-orcid":false,"given":"Stefania","family":"Cannito","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Bocca","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Maggiora","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Bevacqua","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6518-7089","authenticated-orcid":false,"given":"Chiara","family":"Rosso","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medical Science, University of Torino, 10154 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Bugianesi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medical Science, University of Torino, 10154 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4738-7049","authenticated-orcid":false,"given":"Emanuele","family":"Albano","sequence":"additional","affiliation":[{"name":"Department of Health Science, University of East Piedmont, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Novo","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-5141","authenticated-orcid":false,"given":"Maurizio","family":"Parola","sequence":"additional","affiliation":[{"name":"Department Clinical and Biological Science, Unit of Experimental Medicine and Clinical Pathology, University of Torino, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.mam.2007.09.002","article-title":"Myofibroblast-like cells in liver fibrogenesis: Emerging concepts in a rapidly moving scenario","volume":"29","author":"Parola","year":"2008","journal-title":"Mol. Asp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1136\/gutjnl-2014-306842","article-title":"Pathobiology of liver fibrosis: A translational success story","volume":"64","author":"Lee","year":"2015","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/j.jhep.2015.02.039","article-title":"Hepatic fibrosis: Concept to treatment","volume":"62","author":"Trautwein","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.abb.2014.02.015","article-title":"Cellular and molecular mechanisms in liver fibrogenesis","volume":"548","author":"Novo","year":"2014","journal-title":"Arch. Biochem. Biophys"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1002\/hep.23405","article-title":"Portal fibroblasts: Underappreciated mediators of biliary fibrosis","volume":"51","author":"Dranoff","year":"2010","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3181\/0707-MR-190","article-title":"Mechanisms of fibrogenesis","volume":"233","author":"Kisseleva","year":"2008","journal-title":"Exp. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"G881","DOI":"10.1152\/ajpgi.00289.2013","article-title":"Evidence for and against epithelial-to-mesenchymal transition in the liver","volume":"305","author":"Xie","year":"2013","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/hep.23368","article-title":"Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice","volume":"51","author":"Taura","year":"2010","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1053\/j.gastro.2010.05.005","article-title":"Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice","volume":"139","author":"Scholten","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1002\/hep.24206","article-title":"Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis","volume":"53","author":"Chu","year":"2011","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/stem.642","article-title":"Dissection of the biphasic nature of hypoxia-induced motogenic action in bone marrow-derived human mesenchymal stem cells","volume":"29","author":"Busletta","year":"2011","journal-title":"Stem Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.jhep.2010.09.022","article-title":"Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells","volume":"54","author":"Novo","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1055\/s-2001-17554","article-title":"Cytokine receptors and signaling in hepatic stellate cells","volume":"21","author":"Pinzani","year":"2001","journal-title":"Sem. Liver Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis","volume":"112","author":"Bataller","year":"2003","journal-title":"J. Clin. Invest."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/hep.20683","article-title":"Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism","volume":"41","author":"Galli","year":"2005","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.2353\/ajpath.2007.060887","article-title":"Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells","volume":"170","author":"Novo","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jhep.2005.04.020","article-title":"Expression of oncostatin M and its receptors in normal and cirrhotic human liver","volume":"43","author":"Znoyko","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/hep.22928","article-title":"Hypoxia-inducible factor 1alpha is up-regulated by oncostatin M and participates in oncostatin M signaling","volume":"50","author":"Vollmer","year":"2009","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.4049\/jimmunol.162.9.5547","article-title":"Regulation of inflammatory responses by oncostatin M","volume":"162","author":"Wallace","year":"1999","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/labinvest.2011.47","article-title":"Oncostatin M produced in kupffer cells in response to pge2: Possible contributor to hepatic insulin resistance and steatosis","volume":"91","author":"Henkel","year":"2011","journal-title":"Lab. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0168-8278(00)80066-5","article-title":"Oncostatin M: A cytokine upregulated in human cirrhosis, increases collagen production by human hepatic stellate cells","volume":"32","author":"Levy","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1359-6101(00)00003-4","article-title":"Role of oncostatin M in hematopoiesis and liver development","volume":"11","author":"Miyajima","year":"2000","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/hep.29421","article-title":"Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice","volume":"67","author":"Matsuda","year":"2017","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1002\/hep.29754","article-title":"Hypoxia-inducible factor 2\u03b1 drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine-rich glycoprotein","volume":"67","author":"Morello","year":"2018","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1002\/path.3005","article-title":"The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells","volume":"226","author":"Novo","year":"2012","journal-title":"J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1600-065X.2007.00560.x","article-title":"From death receptor to reactive oxygen species and c-Jun N terminal protein kinase: The receptor-interacting protein 1 odyssey","volume":"220","author":"Temkin","year":"2007","journal-title":"Immunol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1755-1536-1-5","article-title":"Redox mechanisms in hepatic chronic wound healing and fibrogenesis","volume":"1","author":"Novo","year":"2008","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1161\/01.ATV.21.3.321","article-title":"Reactive oxygen species regulate heat-shock protein 70 via the JAK\/STAT pathway","volume":"21","author":"Madamanchi","year":"2001","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"903","DOI":"10.3892\/ijmm.2016.2692","article-title":"Targeted blockade of JAK\/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells","volume":"38","author":"Gu","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4292","DOI":"10.1074\/jbc.M308351200","article-title":"Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: Respective roles of the JAK\/STAT and JAK mediated H2O2-dependant MAPK pathways","volume":"279","author":"Cao","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2045-3701-1-14","article-title":"Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: Involvement of hepatocyte STAT3 in TIMP 1 production","volume":"1","author":"Wang","year":"2011","journal-title":"Cell Biosci."},{"key":"ref_33","first-page":"C1481","article-title":"Role of FAK phosphorylation in hypoxia-induced hMSCs migration: Involvement of VEGF as well as MAPKs and eNOS pathways","volume":"301","author":"Lee","year":"2011","journal-title":"Am. J. Physiol Cell Physiol."},{"key":"ref_34","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."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/1\/28\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:44:12Z","timestamp":1760190252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/1\/28"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,20]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["cells9010028"],"URL":"https:\/\/doi.org\/10.3390\/cells9010028","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,20]]}}}