A high-throughput microphysiological system to quantify key events leading to liver fibrosis
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Autor:innen
Autor:in (Körperschaft)
Publikationsdatum
12.2025
Typ der Arbeit
Studiengang
Typ
01A - Beitrag in wissenschaftlicher Zeitschrift
Herausgeber:innen
Herausgeber:in (Körperschaft)
Betreuer:in
Übergeordnetes Werk
Toxicology
Themenheft
DOI der Originalpublikation
Link
Reihe / Serie
Reihennummer
Jahrgang / Band
518
Ausgabe / Nummer
Seiten / Dauer
154248
Patentnummer
Verlag / Herausgebende Institution
Elsevier
Verlagsort / Veranstaltungsort
Auflage
Version
Programmiersprache
Abtretungsempfänger:in
Praxispartner:in/Auftraggeber:in
Zusammenfassung
New approach methodologies (NAMs), including microphysiological systems (MPS), are emerging as alternatives to animal testing. In the liver, chronic hepatocellular damage can progress to fibrosis, which has been described by an Adverse Outcome Pathway (AOP). However, standardized in vitro models that capture and quantify key AOP events and cell-cell interactions are lacking. We developed a scalable liver fibrosis model using the 384-well Akura™ Twin microplate featuring 168 interconnected well pairs. We studied fibrosis progression by seeding HepaRG microtissues (MTs), with or without THP-1 cells in alpha wells and hepatic stellate cell (hTERT-HSC) MTs in beta wells. Cell health and metabolic activity were monitored via specific sensors that detect glucose and lactate levels. Transforming growth factor beta 1 (TGF-β1), methotrexate (MTX) and acetaminophen (APAP) reduced albumin production, indicating hepatocellular injury. TGF-β1 activated THP-1, increasing ALOX5AP, TREM2, and TGF-β1 mRNA expression. PAI-1 protein levels increased following treatment with TGF-β1, particularly in HepaRG-THP-1 co-cultures. In hTERT-HSCs, TGF-β1 also induced expression of fibrosis markers (ACTA2, COL1A1, COL3A1 and FN1) and increased stress fibers and fibronectin expression. Extracellular matrix remodeling was confirmed by elevated Pro-Collagen 1A1 and CTGF protein levels upon TGF-β1 treatment. The Akura™ Twin platform enables high-throughput modeling of liver fibrosis, mimicking the key events of the liver fibrosis AOP. This model, combining a high-throughput MPS with established cell lines, offers a promising tool to investigate fibrosis mechanisms and advancing quantitative AOP development. Journal: Toxicology (Special Issue: Hepatotoxicity: mechanisms and animal-free prediction models).
Schlagwörter
AOP, Liver fibrosis, MPS, NAMs
Fachgebiet (DDC)
Veranstaltung
Startdatum der Ausstellung
Enddatum der Ausstellung
Startdatum der Konferenz
Enddatum der Konferenz
Datum der letzten Prüfung
ISBN
ISSN
0300-483X
Sprache
Englisch
Während FHNW Zugehörigkeit erstellt
Ja
Zukunftsfelder FHNW
Publikationsstatus
Veröffentlicht
Begutachtung
Peer-Review der ganzen Publikation
Open Access-Status
Hybrid
Lizenz
Zitation
Schmidt, S., & Suter-Dick, L. (2025). A high-throughput microphysiological system to quantify key events leading to liver fibrosis. Toxicology, 518, 154248. https://doi.org/10.1016/j.tox.2025.154248