Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms23169380
Keywords
hepatic stellate cell; liver fibrosis; microRNA; miR-223; cytoskeleton; mechanotransduction; organoid model
Funding
- Office of the Permanent Secretary, Ministry of Higher Education, Science, Research, and Innovation [RGNS 64-005]
- Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University [RA 64/033]
- Grants for Development of New Faculty Staff, Ratchadapiseksompotch Endowment Fund, Chulalongkorn University [DNS 64_006_30_001_1]
- Asahi Glass Foundation, Thailand Research Fund (TRF) Senior Research Scholar [RTA6280004]
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University
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miR-223 suppresses fibrogenesis and cellular proliferation while promoting quiescent features in human HSCs. This is mediated by negative regulation of smooth muscle alpha-actin (alpha-SMA) expression, leading to reduced cytoskeletal activity. Ectopic expression of miR-223 attenuates fibrogenesis in human liver injury models, suggesting its potential as an antifibrotic therapy.
MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate target mRNA expression, and altered expression of miRNAs is associated with liver pathological conditions. Recent studies in animal models have shown neutrophil/myeloid-specific microRNA-223 (miR-223) as a key regulator in the development of various liver diseases including fibrosis, where hepatic stellate cells (HSCs) are the key player in pathogenesis. However, the precise roles of miR-223 in human HSCs and its therapeutic potential to control fibrosis remain largely unexplored. Using primary human HSCs, we demonstrated that miR-223 suppressed the fibrogenic program and cellular proliferation while promoting features of quiescent HSCs including lipid re-accumulation and retinol storage. Furthermore, induction of miR-223 in HSCs decreased cellular motility and contraction. Mechanistically, miR-223 negatively regulated expression of smooth muscle alpha-actin (alpha-SMA) and thus reduced cytoskeletal activity, which is known to promote amplification of fibrogenic signals. Restoration of alpha-SMA in miR-223-overexpressing HSCs alleviated the antifibrotic effects of miR-223. Finally, to explore the therapeutic potential of miR-233 in liver fibrosis, we generated co-cultured organoids of HSCs with Huh7 hepatoma cells and challenged them with acetaminophen (APAP) or palmitic acid (PA) to induce hepatotoxicity. We showed that ectopic expression of miR-223 in HSCs attenuated fibrogenesis in the two human organoid models of liver injury, suggesting its potential application in antifibrotic therapy.
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