- Koyama, Yukinori;
- Wang, Ping;
- Liang, Shuang;
- Iwaisako, Keiko;
- Liu, Xiao;
- Xu, Jun;
- Zhang, Mingjun;
- Sun, Mengxi;
- Cong, Min;
- Karin, Daniel;
- Taura, Kojiro;
- Benner, Chris;
- Heinz, Sven;
- Bera, Tapan;
- Brenner, David A;
- Kisseleva, Tatiana
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-β1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGFβRI 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.