Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis.
Takahiro NishioYukinori KoyamaXiao LiuSara B RosenthalGen YamamotoHiroaki FujiJacopo BaglieriNa LiLaura N BrennerKeiko IwaisakoKojiro TauraJames S HagoodNicholas F LaRussoTapan K BeraIra H PastanDavid A BrennerTatiana KisselevaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- liver fibrosis
- endothelial cells
- high glucose
- extracellular matrix
- induced pluripotent stem cells
- pluripotent stem cells
- high fat diet induced
- gene expression
- liver injury
- copy number
- oxidative stress
- type diabetes
- adipose tissue
- mass spectrometry
- skeletal muscle
- bone marrow
- smoking cessation
- atomic force microscopy