Journal Article

MicroRNA-223 restricts liver fibrosis by inhibiting the TAZ-IHH-GLI2 and PDGF signaling pathways via the crosstalk of multiple liver cell types

Park, Seol Hee, Fu, Yaojie, Seo, Wonhyo, Wang, Xiaolin, Gao, Bin, Feng, Dechun, He, Yong, Hwang, Seonghwan, Rodrigues, Robim M.

2021

Overview

Liver fibrosis is a common consequence of chronic liver injury and is characterized by the accumulation of extracellular matrix mainly generated from activated hepatic stellate cells (HSCs). At present, the mechanisms underlying liver fibrogenesis remain obscure and effective pharmacological therapies are lacking. Neutrophil-specific microRNA-223 (miR-223) plays an important role in controlling the development of various liver diseases; however, its role in HSC activation and liver fibrosis remains unclear. Liver fibrosis was induced by chronic carbon tetrachloride (CCl ) injection of miR-223 knockout (miR-223KO) mice and littermate wild-type controls. MiR-223 was overexpressed in cultured HSCs to determine its function and targets during HSC activation and proliferation. The expression of miR-223 and pri-miR-223 was examined in primary HSCs isolated from CCl -treated mice and in cultured HSCs. The communication between HSCs and neutrophils was studied by performing co-culture experiments. Genetic deletion of miR-223 exacerbated chronic CCl -induced liver fibrosis. Administration of miR-223 inhibited liver fibrosis by inhibiting the transcriptional coactivator with PDZ-binding motif (TAZ)-Indian hedgehog (IHH)-GLI Family Zinc Finger 2 (GLI2) pathway via the crosstalk between hepatocytes and HSCs. Overexpression of miR-223 also directly attenuated as well as platelet-derived growth factor receptor α/β ( ) expression in HSCs, thereby suppressing HSC activation and proliferation. The expression of pri-miR-223 and miR-223 was downregulated during HSC activation . Expression of pri-miR-223 was also decreased in activated HSCs in fibrotic livers but mature miR-223 expression was not reduced. Finally, in co-culture experiments, activated HSCs were able to take up miR-223-enriched extracellular vesicles from neutrophils, resulting in elevation of miR-223. MiR-223 restricts liver fibrosis by targeting multiple genes in hepatocytes and HSCs, providing potential therapeutic targets for the treatment of liver fibrosis.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Acyltransferases - metabolism / Adenoviruses / Alcoholism / Animals / Antibodies / Carbon tetrachloride / Carbon Tetrachloride Poisoning - metabolism / Cell culture / Cell Line / Crosstalk / Experiments / Extracellular matrix / Extracellular Vesicles - metabolism / Fibrosis / Gene expression / Growth factors / Hedgehog protein / Hedgehog Proteins - metabolism / Hepatic Stellate Cells - metabolism / Hepatocytes / Hepatocytes - metabolism / Humans / Laboratories / Leukocytes (neutrophilic) / Liver / Liver Cirrhosis - metabolism / Liver diseases / Manufacturers / Medical research / Mice / Mice, Knockout / MicroRNAs / MicroRNAs - metabolism / miRNA / Neutrophils / Penicillin / Platelet-derived growth factor / Receptor Cross-Talk / Receptors, Platelet-Derived Growth Factor - metabolism / Research Paper / Ribonucleic acid / RNA / Signal Transduction / Stellate cells / Therapeutic targets / Transcription / Zinc Finger Protein Gli2 - metabolism / Zinc finger proteins