Modeling alcohol-associated liver disease in a human Liver-Chip
Janna Nawroth, Debora B. Petropolis, Dimitris V. Manatakis, Tengku Ibrahim Maulana, Gabriel Burchett, Katharina Schlünder, Anke Witt, Abhishek Shukla, Konstantia Kodella, Janey Ronxhi, Gauri Kulkarni, Geraldine A. Hamilton, Ekihiro Seki, Shelly C. Lu, Katia Karalis
Abstract
Alcohol-associated liver disease (ALD) is a global health issue and leads to progressive liver injury, comorbidities, and increased mortality. Human-relevant preclinical models of ALD are urgently needed. Here, we leverage a triculture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi to model ALD employing human-relevant blood alcohol concentrations (BACs) and multimodal profiling of clinically relevant endpoints. Our Liver-Chip recapitulates established ALD markers in response to 48 h of exposure to ethanol, including lipid accumulation and oxidative stress, in a concentration-dependent manner and supports the study of secondary insults, such as high blood endotoxin levels. We show that remodeling of the bile canalicular network can provide an in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a powerful platform for modeling alcohol-induced liver injury with the potential for direct translation to clinical research and evaluation of patient-specific responses.