iPSC-derived cardiac organoids for drug cardiotoxicity evaluation and efficacy prediction in myocardial infarction and cardiac hypertrophy models

BACKGROUND: Cardiac organoids (COs) derived from induced pluripotent stem cells (iPSCs) constitute a three-dimensional microphysiological system that more faithfully recapitulates the structural and functional complexity of human heart tissues compared to traditional two-dimensional cultures or animal models. Therefore, it highlights the significance of iPSC-derived COs in providing more precise platform for assessing drug cytotoxicity, cardiac functional toxicity, developmental toxicity, and therapeutic efficacy in disease models. METHODS: Human iPSCs, after generation from somatic cells using reprogramming factors, were differentiated into COs using dynamic culture system. COs were characterized by cell composition, structure, spontaneous beating, electrophysiological properties. Furthermore, drug cytotoxicity was evaluated by assessing cell viability and lactate dehydrogenase release after exposure of COs to doxorubicin. Cardiac functional toxicity was assessed by monitoring changes in beating after exposure to different compounds. In addition, developmental toxicity was tested using thalidomide. Finally, cardioprotective drug efficacy was evaluated based on the construction of myocardial infarction (MI) and cardiac hypertrophy (CH) models. RESULTS: The reprogrammed iPSCs have successfully generated COs with complex structure and function. Myocardial toxicity induced by anthracycline drugs was faithfully reproduced in organoids. This work also examined the effects of isoproterenol, MYK461, E-4031, and nifedipine on cardiac beating. Long-term exposure to thalidomide triggered abnormal atrial-ventricular differentiation in COs. In MI model, cyclosporine A exerted cardioprotective effects by downregulating apoptosis and inflammation. In CH model, on the other hand, apocynin outperformed metoprolol in alleviating Ang II-induced cardiac hypertrophy. CONCLUSIONS: This study establishes an efficient and stable method for generating uniform and functionally mature COs by utilising dynamic culture systems. Also, we proposes a reliable approach for drug-induced cardiotoxicity assessment and efficacy evaluation on the organoid platform, offering a multipurpose and cutting-edge tool for cardiac drug development.