Microrna-223 restricts liver fibrosis by inhibiting the taz-ihh-gli2 and pdgf signaling pathways via the crosstalk of multiple liver cell types

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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background & Aims: 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. Methods: Liver fibrosis was induced by chronic carbon tetrachloride (CCl4) 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 CCl4-treated mice and in cultured HSCs. The communication between HSCs and neutrophils was studied by performing in vitro co-culture experiments. Results: Genetic deletion of miR-223 exacerbated chronic CCl4-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 Gli2 as well as platelet-derived growth factor receptor α/β (Pdgfra/b) expression in HSCs, thereby suppressing HSC activation and proliferation. The expression of pri-miR-223 and miR-223 was downregulated during HSC activation in vitro. Expression of pri-miR-223 was also decreased in activated HSCs in vivo 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. Conclusion: MiR-223 restricts liver fibrosis by targeting multiple genes in hepatocytes and HSCs, providing potential therapeutic targets for the treatment of liver fibrosis.

Original languageEnglish
Pages (from-to)1153-1167
Number of pages15
JournalInternational Journal of Biological Sciences
Volume17
Issue number4
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
This work was supported by the intramural program of NIAAA, NIH (B.G.). Dr. Xiaolin Wang was supported by a Fellowship from Ruijin Hospital when she performed experiments at the NIAAA during 2019-2021.

Publisher Copyright:
© The author(s).

Keywords

  • Gli2
  • HSC
  • Liver fibrosis
  • MiR-223
  • PDGFRα/β

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