{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:17:34Z","timestamp":1785115054048,"version":"3.55.0"},"reference-count":81,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011039","name":"Swiss Centre for Applied Human Toxicology","doi-asserted-by":"publisher","award":["Hepatotoxicity Group"],"award-info":[{"award-number":["Hepatotoxicity Group"]}],"id":[{"id":"10.13039\/501100011039","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013in 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 \u03b1-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.<\/jats:p>","DOI":"10.3390\/ijms22189799","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T10:31:34Z","timestamp":1631269894000},"page":"9799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5955-2596","authenticated-orcid":false,"given":"Catherine Jane","family":"Messner","sequence":"first","affiliation":[{"name":"School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, CH-4132 Muttenz, Switzerland"},{"name":"Department of Pharmaceutical Sciences, University of Basel, CH-4001 Basel, Switzerland"},{"name":"Swiss Centre for Applied Human Toxicology (SCAHT), CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7809-6343","authenticated-orcid":false,"given":"Saskia","family":"Schmidt","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, CH-4132 Muttenz, Switzerland"},{"name":"Department of Pharmaceutical Sciences, University of Basel, CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"\u00d6zkul","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, CH-4132 Muttenz, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Gaiser","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, CH-4132 Muttenz, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Terracciano","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Basel, CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8347-4145","authenticated-orcid":false,"given":"Stephan","family":"Kr\u00e4henb\u00fchl","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Basel, CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1449-3913","authenticated-orcid":false,"given":"Laura","family":"Suter-Dick","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, CH-4132 Muttenz, Switzerland"},{"name":"Swiss Centre for Applied Human Toxicology (SCAHT), CH-4001 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s00204-016-1814-8","article-title":"Adverse Outcome Pathway Development from Protein Alkylation to Liver Fibrosis","volume":"91","author":"Horvat","year":"2017","journal-title":"Arch. 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