{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:18:24Z","timestamp":1790183904169,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","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","award":["Translational Research Program A111"],"award-info":[{"award-number":["Translational Research Program A111"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Exploratory Research 24659367"],"award-info":[{"award-number":["Exploratory Research 24659367"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Scientific Research (B) 17H04161"],"award-info":[{"award-number":["Scientific Research (B) 17H04161"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Scientific Research (B) 26293174"],"award-info":[{"award-number":["Scientific Research (B) 26293174"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin \u03b1\u2010subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture\u2010activated HSCs and specifically expressed across fibroblast linages was the \u03b18 subunit. An anti\u2010\u03b18 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl<jats:sub>4<\/jats:sub> treatment), non\u2010alcoholic steatohepatitis\u2010associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and \u03b1\u2010smooth muscle actin) were improved following the mAb injection. We also CCl<jats:sub>4<\/jats:sub>\u2010treated mice with inducible <jats:italic>Itga8\u2212\/\u2212<\/jats:italic>; these mice were protected from increased hydroxyproline levels. Furthermore, <jats:italic>ITGA8<\/jats:italic> was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC \u03b18 suppressed and enhanced myofibroblast differentiation, respectively, and HSC\/fibroblast \u03b18 activated latent TGF\u03b2. Finally, integrin \u03b18\u03b21 potentially fulfils the growing need for anti\u2010fibrotic drugs and is an integrin not to be ignored. \u00a9 2021 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5618","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T03:43:08Z","timestamp":1610682188000},"page":"366-373","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Induced hepatic stellate cell integrin, \u03b18\u03b21, enhances cellular contractility and <scp>TGF\u03b2<\/scp> activity in liver fibrosis"],"prefix":"10.1002","volume":"253","author":[{"given":"Norihisa","family":"Nishimichi","sequence":"first","affiliation":[{"name":"Integrin\u2010Matrix Biomedical Science Translational Research Center, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Tsujino","sequence":"additional","affiliation":[{"name":"Lung Biology Center, Department of Medicine Cardiovascular Research Institute, University of California San Francisco (UCSF)  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keishi","family":"Kanno","sequence":"additional","affiliation":[{"name":"General Internal Medicine Hiroshima University Hospital, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Sentani","sequence":"additional","affiliation":[{"name":"Molecular Pathology Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Gastroenterological and Transplant Surgery Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Chayama","sequence":"additional","affiliation":[{"name":"Gastroenterology and Metabolism Graduate School of Biomedical and Health Sciences, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Lung Biology Center, Department of Medicine Cardiovascular Research Institute, University of California San Francisco (UCSF)  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-4377","authenticated-orcid":false,"given":"Yasuyuki","family":"Yokosaki","sequence":"additional","affiliation":[{"name":"Integrin\u2010Matrix Biomedical Science Translational Research Center, Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004700"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb07776.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65066-3"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80545-0"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep13756"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81903-0"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajh.2008.309"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0048362"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197937"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1996.v110.pm8613002"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116769"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sdata.2017.105"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900200200"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3282"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201800109R"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13063"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.01.014"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/74286"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.07.028"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.024"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.017"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)37465-3"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw995"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99435"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2010.00569.x"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.10887"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/iep.12008"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840190629"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.51.36328"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep03243"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-7-123"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5618","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5618","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5618","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:56:18Z","timestamp":1761058578000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1002\/path.5618"],"URL":"https:\/\/doi.org\/10.1002\/path.5618","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,19]]},"assertion":[{"value":"2020-11-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}