New CRC publication in Advanced Science:

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease affecting more than one quarter of humankind. This study by Adrien Guillot, Frank Tacke and their teams (project B05) elaborates on a multicellular biochip-based liver sinusoid model to mimic acute liver injury and MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. To this end, liver cell types with key roles in liver disease initiation and progression were seeded in an artificial, biocompatible biochip, and functional assays were performed to evaluate their relevance in disease modelling.

More specifically, 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 freshly isolated circulating immune cells (CICs) from blood. Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug-induced liver injury and MASLD, respectively. APAP exposure induces cell death in the LoC and increases 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.

Overall, this study demonstrates the relevance of in vitro, multicellular and dynamic models for the study of the mechanisms involved in liver disease and paves the way for further developments in preclinical drug exploration.

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