Development of drug toxicity evaluation platform using hiPSC-derived cardiac organoids

Cardiotoxicity is a critical aspect of safety evaluation in drug development. Traditional cardiotoxicity assessment methods rely primarily on animal models and 2D cell culture systems, which fail to replicate the complex physiological characteristics of human cardiac tissue fully. This study aims to generate human Cardiac Organoids (hCOs) derived from human induced Pluripotent Stem Cells (hiPSCs) and to use them to enhance the sensitivity of drug testing. hCOs were successfully cultured for up to 12 weeks, with a stable increase in heart rate observed over the cultivation period. Differentiation conditions were optimized by confirming the expression of cardiac markers (TNNT2), smooth muscle cell markers (aSMA), fibroblast markers (VIM), and endothelial markers (PECAM). The differentiation rate into cardiomyocytes was higher than that of conventional 2D cell culture methods. In calcium imaging using the positive drug nifedipine, the intensity of the calcium signal response of hCOs was confirmed to change depending on the concentration (1, 5, 10uM). This can be inferred that hCOs well reflects changes in various ion channels. Utilizing optimized hCOs conditions, we measured the changes in BPM induced by positive (Quinidine, Moxifloxacin, Nifedipine, E-4031), false positive (Diltiazem), false negative (Bepridil), and negative (Levofloxacin) drugs, comparing these to existing iCM data. The results demonstrated that hCOs exhibited more sensitive changes, suggesting that cardiac organoids can more sensitively and accurately reflect drug-induced cardiotoxicity than traditional 2D cell culture systems. This study presents a cardiotoxicity assessment platform using human-derived cardiac organoids. This approach can enhance the accuracy of cardiotoxicity assessment in the early stages of drug development, ultimately contributing to the development of safe and effective new drugs. Future research will measure electrophysiological changes to further optimize the evaluation platform and present an advanced cardiotoxicity evaluation platform.

This research was supported by a grant (22213MFDS391) from Ministry of Food and Drug Safety in 2024.