A high-throughput microphysiological system to quantify key events leading to liver fibrosis
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Author (Corporation)
Publication date
12.2025
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01A - Journal article
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Parent work
Toxicology
Special issue
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Series number
Volume
518
Issue / Number
Pages / Duration
154248
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Publisher / Publishing institution
Elsevier
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Abstract
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).
Keywords
AOP, Liver fibrosis, MPS, NAMs
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ISBN
ISSN
0300-483X
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Hybrid
License
Citation
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