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
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
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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

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Figure 10

Regulation of FGF signaling pathways in WT aPFs.

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Regulation of FGF signaling pathways in WT aPFs. (A) Immortalized WT and...
(A) Immortalized WT and Msln–/– aPFs (105/well) were pretreated for 20 minutes with DMSO, inhibitor-JAK2 (i-JAK2) (TG-101348, 1 μM), or inhibitor-AKT (i-AKT) (0.5 μM), or with (B) AZD1480 (1 μM) or U0126 (5 μM) and then stimulated with or without FGF (2 ng/ml). Representative immunoblots are shown in A and B. (C) WT and Msln–/– aPFs (105/well) were pretreated for 20 minutes with DMSO or AZD1480 (1 μM) and subjected to a 12-hour scratch assay. Proliferation and migration of WT and Msln–/– aPFs were blocked by AZD1480. Representative fluorescent (Col-GFP) images of more than 3 independent experiments are shown (original magnification, ×10). (D) Proposed model of MSLN regulation of FGF signaling. Binding of FGF to FGFR1 results in activation of the JAK2/STAT3 signaling pathway, upregulation of cyclin D, and proliferation of WT aPFs. Subsequently, phosphorylation (p) of AKT is required for the degradation of FGFR1 in WT aPFs. In turn, Msln–/– aPFs exhibit a defect in AKT phosphorylation, which results in compensatory phosphorylation of ERK1/2 and a failure to properly express and degrade FGFR1. In addition, FGF-inducible activation of JAK2 and STAT3 is impaired in Msln–/– aPFs, and basal proliferation of Msln–/– aPFs is mediated by ERK1/2-dependent phosphorylation of STAT3. Overall, the MSLN/MUC16/AKT pathway is a key regulator of cholestasis-induced proliferation of WT aPFs/myofibroblasts. The loss of AKT activation is associated with an inability of Msln–/– aPFs to mount FGF-mediated responses (see also Supplemental Figure 8).