@article{a431d5d1262543f3b4bdafc01f751750,
title = "Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis",
abstract = "Cholestatic liver fibrosis is caused by obstruction of the biliary tract and is associated with early activation of portal fibroblasts (PFs) that express Thy-1, fibulin 2, and the recently identified marker mesothelin (MSLN). Here, we have demonstrated that activated PFs (aPFs) and myofibroblasts play a critical role in the pathogenesis of liver fibrosis induced by bile duct ligation (BDL). Conditional ablation of MSLN+ aPFs in BDL-injured mice attenuated liver fibrosis by approximately 50%. Similar results were observed in MSLN-deficient mice (Msln-/-mice) or mice deficient in the MSLN ligand mucin 16 (Muc16-/-mice). In vitro analysis revealed that MSLN regulates TGF-?1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGF?RI complex. MSLN also facilitated the FGF-mediated proliferation of WT aPFs. Therapeutic administration of anti-MSLN-blocking Abs attenuated BDL-induced fibrosis in WT mice. Liver specimens from patients with cholestatic liver fibrosis had increased numbers of MSLN+ aPFs/myofibroblasts, suggesting that MSLN may be a potential target for antifibrotic therapy.",
author = "Yukinori Koyama and Ping Wang and Shuang Liang and Keiko Iwaisako and Xiao Liu and Jun Xu and Mingjun Zhang and Mengxi Sun and Min Cong and Daniel Karin and Kojiro Taura and Chris Benner and Sven Heinz and Tapan Bera and Brenner, {David A.} and Tatiana Kisseleva",
note = "Funding Information: Acknowledgments We thank Gianfranco D. Alpini (Baylor Scott & White Healthcare, Temple, Texas, USA) for providing mRNA from isolated cholangiocytes. We thank James S. Hagood (UCSD, La Jolla, California, USA) and Yuval Rinkevich (Institute of Lung Biology and Disease [iLBD] Helmholtz Zentrum M{\"u}nchen, Munich, Germany) for providing Thy-1/ and MslnER-Cre mice. We are grateful to Koji Taniguchi (Keio University, Tokyo, Japan) for his technical support on confocal microscopy. We thank Karin Diggle (UCSD, La Jolla, California, USA) for her dedicated management of our laboratory. This research was supported by the NIH (AA022614, DK099205, DK101737, DK111866, AA011999, ES010337, AA021856, and GM041804); the Japanese Ministry of Health, Labour and Welfare; and the American Liver Foundation. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.",
year = "2017",
month = apr,
day = "3",
doi = "10.1172/JCI88845",
language = "English (US)",
volume = "127",
pages = "1254--1270",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",
}