Cargando…
Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation
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 de...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464755/ https://www.ncbi.nlm.nih.gov/pubmed/34575957 http://dx.doi.org/10.3390/ijms22189799 |
_version_ | 1784572695259643904 |
---|---|
author | Messner, Catherine Jane Schmidt, Saskia Özkul, Dilek Gaiser, Carine Terracciano, Luigi Krähenbühl, Stephan Suter-Dick, Laura |
author_facet | Messner, Catherine Jane Schmidt, Saskia Özkul, Dilek Gaiser, Carine Terracciano, Luigi Krähenbühl, Stephan Suter-Dick, Laura |
author_sort | Messner, Catherine Jane |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8464755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84647552021-09-27 Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation Messner, Catherine Jane Schmidt, Saskia Özkul, Dilek Gaiser, Carine Terracciano, Luigi Krähenbühl, Stephan Suter-Dick, Laura Int J Mol Sci Article 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. MDPI 2021-09-10 /pmc/articles/PMC8464755/ /pubmed/34575957 http://dx.doi.org/10.3390/ijms22189799 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Messner, Catherine Jane Schmidt, Saskia Özkul, Dilek Gaiser, Carine Terracciano, Luigi Krähenbühl, Stephan Suter-Dick, Laura Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title | Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title_full | Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title_fullStr | Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title_full_unstemmed | Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title_short | Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation |
title_sort | identification of mir-199a-5p, mir-214-3p and mir-99b-5p as fibrosis-specific extracellular biomarkers and promoters of hsc activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464755/ https://www.ncbi.nlm.nih.gov/pubmed/34575957 http://dx.doi.org/10.3390/ijms22189799 |
work_keys_str_mv | AT messnercatherinejane identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT schmidtsaskia identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT ozkuldilek identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT gaisercarine identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT terraccianoluigi identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT krahenbuhlstephan identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation AT suterdicklaura identificationofmir199a5pmir2143pandmir99b5pasfibrosisspecificextracellularbiomarkersandpromotersofhscactivation |