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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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-?1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGF?RI 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.

Original languageEnglish (US)
Pages (from-to)1254-1270
Number of pages17
JournalJournal of Clinical Investigation
Volume127
Issue number4
DOIs
StatePublished - Apr 3 2017
Externally publishedYes

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CA-125 Antigen
Liver Cirrhosis
Fibroblasts
Bile Ducts
Ligation
Myofibroblasts
mesothelin
Biliary Tract
Fibrosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 127, No. 4, 03.04.2017, p. 1254-1270.

Research output: Contribution to journalArticle

Koyama, Y, Wang, P, Liang, S, Iwaisako, K, Liu, X, Xu, J, Zhang, M, Sun, M, Cong, M, Karin, D, Taura, K, Benner, C, Heinz, S, Bera, T, Brenner, DA & Kisseleva, T 2017, 'Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1254-1270. https://doi.org/10.1172/JCI88845
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. / Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 4. pp. 1254-1270.
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