Abstract
Recapitulating in vivo conditions of metabolism remains a challenging subject in biomedical research such as ADME-Tox assays (absorption, distribution, metabolism, excretion, and toxicity). The advanced technologies using 3D co-culture methods enabled researchers to develop cell-cell and cell-extracellular matrix (ECM) interactions similar to the natural liver, resulting in the improvement of the metabolic performance of ex vivo cultured primary hepatocytes (PHs). Although PHs are the best candidates in cell-based drug screening methods, access to these cells is limited. The application of stem cell-derived hepatocyte-like cells (HLCs) could overcome these limitations in high-throughput assessments. However, the functional capacity of HLCs is not enough. Hepatoma cells could be reliable substitutes for PHs and HLCs; however, compared to PHs, their metabolic performance is low. Mimicking the complexity of the liver microenvironment using hepatoma cells and liver-specific stromal cells in a 3D culture condition represents an innovative, accessible, and scalable platform to accelerate drug development if the metabolic capacity of hepatoma cells is enhanced. This can reduce time, costs, and address the ethical concerns related to animal models and pluripotent stem cells. In this manuscript, we showed that mimicking the complexity of the liver microenvironment in a 3D co-culture condition with non-parenchymal cells and improving the metabolic performance of hepatoma cells represents an innovative and accessible platform to accelerate drug discovery and development.