Dissecting Acute Drug-Induced Hepatotoxicity and Therapeutic Responses of Steatotic Liver Disease Using Primary Mouse Liver and Blood Cells in a Liver-On-A-Chip Model.
NAFLD
NASH
fibrosis
liver diseases
macrophages
microfluidic biochip
steatohepatitis
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
13 Jun 2024
13 Jun 2024
Historique:
revised:
19
04
2024
received:
03
04
2024
medline:
13
6
2024
pubmed:
13
6
2024
entrez:
13
6
2024
Statut:
aheadofprint
Résumé
Metabolic dysfunction-associated steatotic liver disease (MASLD) is hallmarked by hepatic steatosis, cell injury, inflammation, and fibrosis. This study elaborates on a multicellular biochip-based liver sinusoid model to mimic MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. Mouse liver primary hepatocytes, hepatic stellate cells, Kupffer cells, and endothelial cells are seeded in a dual-chamber biocompatible liver-on-a-chip (LoC). The LoC is then perfused with circulating immune cells (CICs). Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug-induced liver injury and MASLD, respectively. As a benchmark for the LoC, multiplex immunofluorescence on livers from APAP-injected and dietary MASLD-induced mice reveals characteristic changes on parenchymal and immune cell populations. APAP exposure induces cell death in the LoC, and increased inflammatory cytokine levels in the circulating perfusate. Under FFA stimulation, lipid accumulation, cellular damage, inflammatory secretome, and fibrogenesis are increased in the LoC, reflecting MASLD. Both injury conditions potentiate CIC migration from the perfusate to the LoC cellular layers. Lanifibranor prevents the onset of inflammation, while resmetirom decreases lipid accumulation in hepatocytes and increases the generation of FFA metabolites in the LoC. This study demonstrates the LoC potential for functional and molecular evaluation of liver disease drug candidates.
Identifiants
pubmed: 38868948
doi: 10.1002/advs.202403516
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2403516Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : ImmunAvatar consortium
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB1382
Organisme : Deutsche Forschungsgemeinschaft
ID : DFGTa434/8-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB/TRR296
Organisme : Deutsche Forschungsgemeinschaft
ID : Project-ID403224013
Informations de copyright
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.
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