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Flow-Based Three-Dimensional Co-Culture Model for Long-Term Hepatotoxicity Prediction
Yoon Young Choi1, Jin-I Seok1, Dong-Sik Kim1
1Department of HBP Surgery & Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul 02841, Korea.
Micromachines
|January 2, 2020
Summary
This study introduces a 3-D liver-on-a-chip model using co-cultured hepatocytes and hepatic stellate cells (HSCs) for predicting drug toxicity. The model enhances liver function and accurately predicts drug-induced liver injury in vitro.
Area of Science:
- * Biomedical Engineering
- * Cell Biology
- * Toxicology
Background:
- * Current in vitro drug toxicity testing models often fail to accurately predict human hepatotoxicity.
- * There is a need for advanced 3-D liver models that mimic the in vivo microenvironment for reliable drug screening.
Purpose of the Study:
- * To develop a size-controllable 3-D co-culture liver model using concave microwell arrays.
- * To investigate the role of hepatic stellate cells (HSCs) in hepatocyte spheroid formation and function.
- * To evaluate the model's efficacy for long-term in vitro drug toxicity and hepatotoxicity prediction.
Main Methods:
- * Development of concave microwell arrays for 3-D co-culture of primary hepatocytes and HSCs (heterospheres).
- * Characterization of spheroid formation and cell-cell interactions using scanning electron microscopy (SEM).
- * Assessment of metabolic functions (albumin, urea secretion) and gene expression (CYP1A2, Mrp1, UGT1A5, CYP3A4).
- * Cytotoxicity evaluation using Lactate dehydrogenase (LDH) release assay and IC50 determination for acetaminophen (AAP) and isoniazid (INH).
Main Results:
- * Co-cultured heterospheres exhibited tighter aggregation and faster formation compared to mono-cultured hepatospheres.
- * Heterospheres demonstrated significantly higher albumin and urea secretion (40% more) than hepatospheres by day 13.
- * The model showed concentration-dependent CYP3A4 induction and increased LDH release upon AAP and INH treatment, consistent with known hepatotoxicity.
- * Calculated IC50 values for AAP and INH indicated the model's utility for cytotoxicity testing.
Conclusions:
- * The 3-D liver-on-a-chip model, incorporating HSCs, closely mimics the in vivo liver microenvironment.
- * This co-culture system enables size-controllable spheroid formation and supports long-term culture.
- * The model demonstrates significant potential for accurate and reliable in vitro prediction of drug-induced hepatotoxicity.
