Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis
Yukinori Koyama ... David A. Brenner, Tatiana Kisseleva
Yukinori Koyama ... David A. Brenner, Tatiana Kisseleva
Published March 13, 2017
Citation Information: J Clin Invest. 2017. doi:10.1172/JCI88845.
View: Text | PDF
Categories: Research Article Gastroenterology

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-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.

Authors

Yukinori Koyama, Ping Wang, Shuang Liang, Keiko Iwaisako, Xiao Liu, Jun Xu, Mingjun Zhang, Mengxi Sun, Min Cong, Daniel Karin, Kojiro Taura, Chris Benner, Sven Heinz, Tapan Bera, David A. Brenner, Tatiana Kisseleva

×
Options: View larger image (or click on image)
Deletion of Msln attenuates the development of cholestatic liver fibrosi...

Figure 1

Deletion of Msln attenuates the development of cholestatic liver fibrosis in mice.

(A–C) Eight-week-old male WT and Msln–/– mice (C57BL/6, n = 10/group, n = 3 independent experiments) underwent sham or BDL operation (for 5 days or 17 days) or treatment with CCl4 (1.5 mo, n = 7/group). Deletion of Msln in mice attenuated BDL-induced (for 5 days) liver fibrosis by approximately 50%. (A) Livers were stained with Picrosirius red, and (B) the positively stained area was quantified as a percentage using ImageJ. (B) Liver function was estimated according to serum ALT and ALP levels (IU/l). (C) mRNA expression of fibrogenic (Col1a1, α-SMA, Tgfb1), inflammatory (F4/80), and aPF-specific (Msln and fibulin 2) genes was determined by qPCR of total liver tissue. Data indicate the fold induction versus sham-operated WT mice. *P < 0.05 and **P < 0.01 , by 2-tailed Student’s t test.