Integrated Isogenic Human Induced Pluripotent Stem Cell-Based Liver and Heart Microphysiological Systems Predict...

Area of Science:

• Biotechnology and Pharmaceutical Sciences
• Stem Cell Technology
• Organ-on-a-Chip Technology

Background:

• Three-dimensional microphysiological systems (MPSs) offer an *in vitro* alternative to traditional drug development models.
• Human induced pluripotent stem cells (hiPSCs) provide a genetically diverse and renewable cell source for MPSs.
• Integrating hiPSC-derived organs in MPSs enables personalized and predictive drug testing.

Purpose of the Study:

• To develop and validate an integrated hiPSC-based liver-cardiac MPS for studying drug-drug interactions (DDIs).
• To investigate the DDI between cisapride and ketoconazole using the integrated MPS.
• To assess the potential of this platform for predicting drug efficacy and toxicity.

Main Methods:

• Construction of a novel liver MPS and a cardiac MPS using the same hiPSC line.
• Integration of the liver and cardiac MPSs to create a connected system.
• Investigation of the interaction between cisapride and ketoconazole, focusing on CYP3A4 inhibition and cardiac arrhythmia.

Main Results:

• Ketoconazole inhibited the metabolic conversion of cisapride to norcisapride in the liver MPS, mimicking *in vivo* drug metabolism.
• The inhibition of cisapride metabolism by ketoconazole led to predicted cardiac arrhythmia in the connected cardiac MPS.
• The results align with known clinical observations of this specific DDI.

Conclusions:

• The integrated hiPSC-based liver-cardiac MPS is a viable platform for screening DDIs.
• This isogenic system facilitates the prediction of drug-induced toxicity and efficacy.
• This approach advances drug development by providing a more human-relevant *in vitro* model.