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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;127(4):1254-1270. https://doi.org/10.1172/JCI88845.
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Research Article Gastroenterology Article has an altmetric score of 1

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

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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 4

Therapeutic administration of anti-MSLN Abs reduces cholestatic fibrosis development in mice.

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Therapeutic administration of anti-MSLN Abs reduces cholestatic fibrosis...
(A) Liver fibrosis was reduced in BDL-injured 8-week-old male collagen α1(I)–GFP (Col-GFP) mice (C57BL/6, n = 10/group, n = 2 independent experiments) that were treated with anti-MSLN–blocking Abs (2 i.p. injections; Ab1: 200 or 400 ng/g BW; Ab2: 400 ng/g BW, administered 24 and 48 hours after BDL) compared with IgG-treated (400 ng/g BW) and Msln–/– mice (n = 3). Micrographs show Picrosirius red, α-SMA, and Col-GFP staining (original magnification, ×4 and ×10). The positively stained area was calculated as a percentage. Col1a1 and α-SMA mRNA expression levels are shown as fold downregulation. *P < 0.05 and **P < 0.01, by ANOVA. (B) Expression of human MSLN mRNA was analyzed by qPCR in liver specimens from patients with BA (n = 6); secondary biliary fibrosis (METAVIR score of F2, n = 5); and HCV fibrosis (METAVIR score of F2, n = 5) versus control livers (n = 4). *P < 0.05, by ANOVA. (See also Supplemental Figure 4.)

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ISSN: 0021-9738 (print), 1558-8238 (online)

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