Artificial MicroRNA-Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice

Human Gene Therapy
Yan JiangHaijian Wang

Abstract

Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. A novel RNAi strategy based on HSC-specific GFAP promoter-driven and lentiviral-expressed artificial microRNAs (amiRNAs) was devised that consists of an microRNA-30a backbone and effective shRNAs against mouse Pdgfrβ and Tgfbr2. Then, its antifibrotic efficacy was tested in primary and cultured HSCs and in mice affected with carbon tetrachloride-induced hepatic fibrosis. The study shows that amiRNA-mediated Pdgfrβ and Tgfbr2 co-silencing inhibits HSC activation and proliferation. After recombinant lentiviral particles were delivered into the liver via tail-vein injection, therapeutic amiRNAs were preferentially expressed in HSCs and efficiently co-knocked down in situ Tgfbr2 and Pdgfrβ expression, which correlates with downregulated expression of target or effector genes of their signaling, which include Pai-1, P70S6K, and D-cyclins. amiRNA-based HSC-specific co-silencing ...Continue Reading

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Citations

Aug 29, 2020·European Journal of Pharmacology·Devaraj Ezhilarasan
Mar 7, 2021·International Journal of Molecular Sciences·Weiyang FanPeibo Li
Sep 3, 2020·Acta Pharmaceutica Sinica. B·Somayeh MahdinlooParvin Zakeri-Milani

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Methods Mentioned

BETA
PCRs
PCR
transfection
density gradient centrifugation
transgenic
acetylation

Software Mentioned

RNAstructure
Image
Image J
Pro Plus

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