Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as fibrosis-specific extracellular biomarkers and promoters of HSC activation
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Authors
Özkul, Dilek
Terraciano, Luigi
Krähenbühl, Stephan
Author (Corporation)
Publication date
2021
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Type
01A - Journal article
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Parent work
International Journal of Molecular Sciences
Special issue
DOI of the original publication
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Series
Series number
Volume
22
Issue / Number
18
Pages / Duration
1-24
Patent number
Publisher / Publishing institution
MDPI
Place of publication / Event location
Basel
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Abstract
Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.
Keywords
3D in vitro model, Liver fibrosis, MicroRNA, Biomarkers, Drug-induced liver injury
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ISBN
ISSN
1661-6596
1422-0067
1422-0067
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Gold
License
Citation
Suter-Dick, L., Messner, C., Özkul, D., Gaiser, C., Schmidt, S., Terraciano, L., & Krähenbühl, S. (2021). Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as fibrosis-specific extracellular biomarkers and promoters of HSC activation. International Journal of Molecular Sciences, 22(18), 1–24. https://doi.org/10.3390/ijms22189799