Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis

J Clin Invest. 2017 Apr 3;127(4):1254-1270. doi: 10.1172/JCI88845. Epub 2017 Mar 13.

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.

MeSH terms

  • Animals
  • CA-125 Antigen / genetics
  • CA-125 Antigen / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • Humans
  • Liver Cirrhosis, Biliary / genetics
  • Liver Cirrhosis, Biliary / metabolism*
  • Liver Cirrhosis, Biliary / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mesothelin
  • Mice
  • Mice, Knockout
  • Signal Transduction*
  • Thy-1 Antigens / genetics
  • Thy-1 Antigens / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism

Substances

  • CA-125 Antigen
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • GPI-Linked Proteins
  • MSLN protein, human
  • MUC16 protein, human
  • MUC16 protein, mouse
  • Membrane Proteins
  • Msln protein, mouse
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Thy-1 Antigens
  • Transforming Growth Factor beta1
  • fibulin 2
  • Mesothelin