Modeling Radiation-induced Cardiovascular Dysfunction with Human iPSC-Derived Engineered Heart Tissues

Low-LET radiation can cause cardiovascular dysfunctions at high-dose rates. For example, photons used in thoracic radiotherapy are known to cause acute cardiac tissue damage with elevated serum cardiac Troponin I level and long-term cardiac complications when delivered as fractionated exposures at high-dose rates. However, the effects of continuous low-dose rate radiation exposure on the heart, which simulate the space radiation environment, have not been well-studied. In this study, we aim to model low-LET space radiation-induced cardiovascular dysfunction using human induced pluripotent stem cell (iPSC)-derived engineered heart tissues (EHTs) exposed to protracted γ-ray irradiation. The investigation of pathophysiological changes in this model may provide insights and guide the development of countermeasures. As a proof-of-principle for the application of this model in drug development, we also tested the protective effect of a mitochondrial-specific antioxidant, MitoTempo, on irradiated EHTs. In this study, EHTs were generated from two healthy iPSC lines (#1 and #2) using an established protocol, comprising of 70% cardiomyocytes (CMs), 15% endothelial cells (ECs) and 15% fibroblasts (FBs). After 10 days, the EHTs were exposed to 137Cs γ-rays continuously at a dose-rate of 9.3 mGy/hour for 5 days. Cells were collected for bulk RNA sequecning from two independent experiments.