| First Author | Koyama Y | Year | 2017 |
| Journal | J Clin Invest | Volume | 127 |
| Issue | 4 | Pages | 1254-1270 |
| PubMed ID | 28287406 | Mgi Jnum | J:243611 |
| Mgi Id | MGI:5909190 | Doi | 10.1172/JCI88845 |
| Citation | Koyama Y, et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127(4):1254-1270 |
| abstractText | 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-beta1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGFbetaRI 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. |
