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In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGF\u03b21\/TGF\u03b2RI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGF\u03b21-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.<\/jats:p>","DOI":"10.3390\/biology11111589","type":"journal-article","created":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T23:45:00Z","timestamp":1667087100000},"page":"1589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury"],"prefix":"10.3390","volume":"11","author":[{"given":"Takahiro","family":"Nishio","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"},{"name":"Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"},{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukinori","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"},{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Fuji","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"},{"name":"Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"},{"name":"Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Iwaisako","sequence":"additional","affiliation":[{"name":"Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe 610-0394, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kojiro","family":"Taura","sequence":"additional","affiliation":[{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"},{"name":"Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etsuro","family":"Hatano","sequence":"additional","affiliation":[{"name":"Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Kisseleva","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/hep.28948","article-title":"The origin of fibrogenic myofibroblasts in fibrotic liver","volume":"65","author":"Kisseleva","year":"2017","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1172\/JCI93563","article-title":"Resolution of organ fibrosis","volume":"128","author":"Jun","year":"2018","journal-title":"J. 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