A Human iPSC-based 3D Microphysiological System for Modeling Cardiac Dysfunction in Microgravity

项目总结

PROJECT SUMMARY Spaceflight has been shown to have negative impacts on the heart, with cardiac arrythmias observed in astronauts and the risk of adverse cardiac events increasing significantly in astronauts who traveled beyond low Earth orbit. Despite these observations, little is known about the underlying mechanistic reasons at the cell and tissue level. To address this, we developed a high-throughput microphysiological engineered heart tissue (EHT) model of human cardiac tissue, derived from human induced pluripotent stem cells (hiPSCs) to study the effects of spaceflight on cardiac cell and tissue structure and function. These EHTs are generated with a biomimetic extracellular matrix composition and stiffness with increased tissue conductivity, which improves overall tissue unction and is more analogous to adult human myocardium than many previous models. During the first phase of the parental grant, these EHTs were launched to the International Space Station (ISS), where contractile forces were measured in real time using a magnet-based force sensor system. Following 28 days in microgravity, tissue contractile function was impaired and mitochondrial dysfunction was observed. During the UH3 phase, a random positioning machine is being used to simulate microgravity and to test attenuating strategies. In this project, we will establish an in-house data management system to rigorously organize the datasets of the parental grant. These datasets will encompass control tissue function of physiologically-relevant tissues in our microphysiological system, tissues under real and simulated microgravity, and results of therapeutic screens on tissue function. It will also include information on strategies to prevent drug absorption in the polymeric components of our system. Once organized, the data will be compatible with, and deposited into, the Microphysiology Systems Database (MPS-Db), where it will be publicly available. Our data will expedite the development of technologies to combat the adverse cardiovascular effects caused by long-term exposure to microgravity. Additionally, the effects of spaceflight on the human body appear to mimic an accelerated aging process, including cardiac deterioration, in the general human population. We expect our data will also facilitate the development of technologies and therapies to attenuate cardiomyopathies on Earth.