Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

Takahiro Nishio, Yukinori Koyama, Xiao Liu, Sara B. Rosenthal, Gen Yamamoto, Hiroaki Fuji, Jacopo Baglieri, Na Li, Laura N. Brenner, Keiko Iwaisako, Kojiro Taura, James S. Hagood, Nicholas F. LaRusso, Tapan K. Bera, Ira Pastan, David A. Brenner, Tatiana Kisseleva

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln/ mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

Original languageEnglish (US)
Article numbere2101270118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number29
DOIs
StatePublished - Jul 20 2021

Keywords

  • Activated portal fibroblasts
  • Cholestatic fibrosis
  • Mesothelin

ASJC Scopus subject areas

  • General

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