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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
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A human liver organoid screening platform for DILI risk prediction
Charles J Zhang1, Sophia R Meyer1, Matthew J O'Meara2
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
Journal of Hepatology
|February 4, 2023
Summary
Human liver organoids (HLOs) offer advanced in vitro models for predicting drug-induced liver injury (DILI). These HLOs, in high-throughput and organ-on-chip systems, show promise for DILI risk assessment and novel drug development.
Area of Science:
- Hepatology and Toxicology
- Stem Cell Biology
- Biotechnology
Background:
- Drug-induced liver injury (DILI) presents significant challenges in clinical trials and post-market drug safety.
- Existing in vitro models lack the complexity to accurately predict DILI across diverse host genetics and clinical factors.
- There is a critical need for improved in vitro models for DILI risk prediction.
Purpose of the Study:
- To evaluate the utility of human liver organoids (HLOs) for high-throughput DILI risk prediction.
- To assess HLOs in an organ-on-chip system for DILI risk assessment.
- To investigate HLOs' capacity to model diverse host genetics and clinical factors in DILI prediction.
Main Methods:
- Human liver organoids (HLOs) were derived from three induced pluripotent stem cell (iPSC) lines.
- HLOs were evaluated on two platforms: dispersed in 384-well plates for high-throughput screening and integrated into a liver-on-chip system.
- Assays included albumin and ALT/AST measurements, morphological profiling, and single-cell transcriptomics to assess liver function and compound cytotoxicity.
Main Results:
- Dispersed HLOs demonstrated comparable DILI predictive capacity to intact HLOs in high-throughput screening, yielding measurable IC50 values.
- On-chip HLOs exhibited enhanced liver-specific functions (albumin production, CYP450 expression) and greater ALT/AST release upon exposure to hepatotoxic drugs compared to dispersed HLOs and primary hepatocytes.
- On-chip HLOs successfully predicted synergistic hepatotoxicity and modeled drug-induced steatosis and mitochondrial perturbation.
Conclusions:
- Both high-throughput and liver-on-chip HLO systems demonstrate enhanced in vivo-like functions for DILI risk assessment.
- These platforms hold potential for predicting DILI and supporting the development of safer novel drugs.
- Further development of patient-derived HLOs is supported for DILI research and potential in vitro diagnostics.
