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

项目摘要 太空飞行已被证明对心脏有负面影响， 宇航员和不良心脏事件的风险显着增加的宇航员谁旅行超过低 地球轨道。尽管有这些观察结果，但对细胞的潜在机制原因知之甚少， 组织水平。为了解决这个问题，我们开发了一种高通量的微生理工程心脏组织（EHT） 来源于人诱导多能干细胞（hiPSC）的人心脏组织模型，以研究 对心脏细胞、组织结构和功能的影响。这些EHT是由一种仿生 细胞外基质成分和硬度，增加组织传导性，从而改善整体组织 并且比许多先前的模型更类似于成人心肌。在第一阶段期间 这些EHT被发射到国际空间站（ISS），在那里收缩 使用基于磁体的力传感器系统来真实的实时测量力。经过28天的微重力， 组织收缩功能受损并观察到线粒体功能障碍。在UH 3阶段， 随机定位机正在被用来模拟微重力和测试衰减战略。在这 我们会建立一个内部数据管理系统，严格整理 父母补助金这些数据集将涵盖我们的研究中生理相关组织的对照组织功能。 微生理系统、真实的和模拟微重力下的组织，以及 组织功能它还将包括防止药物在聚合物中吸收的策略信息。 我们系统的组成部分。一旦组织好，数据将与 微生理学系统数据库（MPS-Db），它将公开提供。我们的数据将加速 开发技术，以消除长期接触 微重力此外，太空飞行对人体的影响似乎模拟了加速老化 过程，包括心脏恶化，在一般人群中。我们希望我们的数据也能帮助 发展技术和疗法来减轻地球上的心肌病。

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.