Effect of Microgravity on Drug Responses Using Engineered Heart Tissues

项目总结 组织工程化器官或功能组织样合体对我们理解 允许细胞在三维(3-D)中迁移、发育和成熟的细胞壁龛。传统的两个- 二维(2D)哺乳动物细胞培养并不代表构成基础的生理环境 以保证正常的细胞功能。3-D环境促进各向同性的细胞间通信，提供细胞外 从结构矩阵脚手架引导，并允许时空重构。我们特别感兴趣的是 应用工程化心脏组织(EHTS)研究微重力对心脏功能的影响。自.以来 这些组织工程平台支持自下而上的多细胞体系结构，关键是 从原始状态理解心脏发育的机制。虽然使用的是动物模型 广泛调查治疗的生物学反应，人类和动物之间的固有差异 生物学加上动物不太可能患人类疾病，限制了验证的能力 研究成果。人类诱导多能干细胞(HiPSCs)已成为 将细胞从胚胎状态驱动到任何体细胞类型。我们实验室的重点和专业知识是 HiPSC来源的心肌细胞(HiPSC-CMS)和心肌病的建模已经对 导致心力衰竭的几种罕见而常见的原因。以维持特定于组织的微环境， 细胞必须在生理相关的3-D细胞外基质(ECM)中培养。在第一阶段(UG3)，我们 将从不同种族的健康患者(高加索人、西班牙人和 非洲裔美国人)。HiPSC-CMS将用于制造我们特征良好的EHT平台，以 了解在微重力和地球重力下影响心脏功能的细胞机制。 暴露在微重力下的样本中，由于心肌减弱而导致的心功能改变将是 与在缺血性心肌病中观察到的分子和电生理疾病模式相匹配。在 第二阶段(UH3)，特征良好的微重力诱导的疾病表型将翻译到心脏上 组织阵列(HTA)以高通量的方式筛选潜在的候选药物。建议进行的研究 将首次揭示驱动心脏组织表型变化的关键功能和分子差异 在微重力影响下的EHT组件。

PROJECT SUMMARY Tissue engineered organs or functional tissue-like ensembles contribute significantly to our understanding of cellular niches that allow cells to migrate, develop and mature in three dimensions (3-D). Conventional two- dimensional (2-D) mammalian cell culture does not represent the physiological environments that form the basis for normal cell function. A 3-D environment promotes isotropic cell-cell communications, provides extracellular guidance from structural matrix scaffolding, and allows spatiotemporal remodelling. Our specific interest is in investigating the effects of microgravity on heart function with the use of Engineered Heart Tissues (EHTs). Since these tissue engineering platforms support multicellular architecture from a ‘bottom-up’ approach, it is critical to understand the mechanisms of heart development from a primordial state. Although animal models are used widely to investigate biological responses to therapeutics, inherent differences between human and animal biology combined with the unlikelihood of animals developing a human disease limit the ability to validate research findings. Human induced pluripotent stem cells (hiPSCs) have emerged as an indispensable tool to drive cells from an embryonic state to any somatic cell type. Our laboratory’s focus and expertise in generating hiPSC-derived cardiomyocytes (hiPSC-CMs) and modelling of cardiomyopathies has yielded deeper insight into several rare and common causes of heart failure. To maintain a tissue-specific microenvironment, dissociated cells must be cultured in a physiologically relevant 3-D extracellular matrix (ECM). In the first phase (UG3), we will generate hiPSC-CMs from healthy patients belonging to diverse racial groups (Caucasians, Hispanics, and African Americans). The hiPSC-CMs will be used to fabricate our well-characterized EHT platforms, to understand cellular mechanisms that affect cardiac function both under microgravity and earth’s gravity. Alterations in cardiac function due to weakened heart muscles in the samples exposed to microgravity will be matched with molecular and electrophysiological disease patterns observed in ischemic cardiomyopathy. In the second phase (UH3), the well-characterized microgravity-induced disease phenotype will be translated on Heart Tissue Arrays (HTA) to screen for potential drug candidates in a high-throughput manner. The proposed study will for the first time reveal key functional and molecular differences that drive phenotypic changes in heart tissues on EHT assemblies under influence of microgravity.