Multi-Cellular Human Liver Organoids for Modeling Metabolic Dysfunction-Associated Steatotic Liver Disease and...

Area of Science:

• Hepatology and Toxicology
• Biomedical Engineering
• Drug Discovery and Development

Background:

• In vitro models are crucial for assessing drug-induced toxicity, especially in metabolic dysfunction-associated steatotic liver disease (MASLD).
• Existing liver organoid systems often fail to replicate key hepatic functions and MASLD pathology.
• There is a need for advanced models that recapitulate human liver physiology and disease states for accurate drug evaluation.

Purpose of the Study:

• To develop a functional, multi-cell type human liver organoid (HML) model.
• To establish a method for inducing MASLD-like features in HML organoids.
• To validate the utility of these organoids for assessing drug-induced liver injury (DILI) in healthy and diseased liver states.

Main Methods:

• Generated 3D human liver organoids (HML) using HepaRG cells, primary human macrophages, and LX-2 hepatic stellate cells.
• Induced MASLD in HML organoids by exposing them to stearic and oleic acids for 9 days.
• Evaluated liver-specific functions, fibrosis markers, and drug-induced liver injury (DILI) using IC50 and benchmark dose calculations.

Main Results:

• The developed HML organoids exhibit key hepatic functions and can be induced to mimic MASLD pathology, including steatosis and fibrogenic responses.
• MASLD-HML organoids retained liver-specific functions and expressed crucial fibrosis markers.
• The organoid model proved effective for standardized evaluation of DILI, enabling IC50 and benchmark dose calculations in MASLD contexts.

Conclusions:

• Human liver organoids (HML) and MASLD-HML organoids offer a robust platform for studying drug metabolism and toxicity.
• These models provide a valuable tool for evaluating drug-induced liver injury (DILI) in both healthy and MASLD conditions.
• The developed model system advances in vitro liver research, supporting safer and more effective drug development.