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-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.forename: Yukinori
authors.initials: Y
authors.lastname: Koyama
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.forename: Mengxi
authors.initials: M
authors.lastname: Sun
authors.forename: Min
authors.initials: M
authors.lastname: Cong
authors.forename: Daniel
authors.initials: D
authors.lastname: Karin
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Sven
authors.initials: S
authors.lastname: Heinz
authors.forename: Tapan
authors.initials: T
authors.lastname: Bera
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kisseleva
mesh_terms: D000818:Animals; D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000090204:Mesothelin; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018394:CA-125 Antigen; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; C451759:MUC16 protein, human; C534798:MUC16 protein, mouse; D008565:Membrane Proteins; C000715528:Msln protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D018800:Thy-1 Antigens; D053773:Transforming Growth Factor beta1; C084612:fibulin 2; D000090204:Mesothelin