Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

人多能干细胞来源的心肌细胞的成熟

• 批准号: 9447662
• 负责人: Chunhui Xu
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447662
• 关键词: Address; Adverse event; Agonist; Arrhythmia; Biogenesis; Birth; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Cycle; Cells; Chemicals; Clinical Research; Consumption; Cues; Data; Developmental Biology; Disease model; Down-Regulation; Drug usage; Fatty Acids; Gene Expression; Generations; Glucose; Glycolysis; Goals; Heart; Human; Human Development; In Vitro; Levocarnitine; Lipids; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mutation; Neonatal; Newborn Infant; Oxygen; PPAR alpha; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmacology; Physiological; Play; Production; Publications; Regenerative Medicine; Regulation; Role; Signal Pathway; Signal Transduction; Source; Stem cells; Testing; Thyronines; Tissue Engineering; Transplantation; cardiac tissue engineering; cardiogenesis; drug discovery; experience; fatty acid oxidation; fetal; heart metabolism; human disease; human model; human pluripotent stem cell; hypoxia inducible factor 1; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; metabolomics; novel; postnatal; preclinical study; response; sensor; transcriptomics

MATURATION OF HUMAN PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES PROJECT SUMMARY Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide a novel and physiologically relevant source of cells that have the potential to be used for in vitro cardiotoxicity testing and disease modeling as well as for the study of in vivo heart development and regenerative medicine. However, compared with primary human CMs, hPSC-CMs are structurally and functionally less mature, which limits their ability to accurately predict cardiotoxicity and model human development and diseases, and may result in adverse events such as arrhythmias upon transplantation. Therefore, improving hPSC-CM maturation is paramount in order to improve applications of these cells. We and other groups have previously demonstrated that efficient CM differentiation from hPSCs can be achieved via mimicking molecular signaling of cardiac induction during in vivo cardiogenesis. In our recent publications, we have also shown that microscale tissue engineering enables reliable generation of 3D cardiac spheres that contain highly enriched hPSC-CMs with enhanced sarcomeric structural maturation. We hypothesize that a multipronged, synergistic approach combining tissue engineering with modulation of multiple molecular signaling pathways can efficiently improve hPSC-CM maturation within short culture durations. With this hypothesis, we aim to enable metabolic and functional maturation of hPSC-CMs by providing the cells with (1) appropriate chemical signals to modulate metabolic maturation and (2) suitable environmental cues to mimic the transition from fetal CMs to postnatal CMs. We expect that this study will lead to the establishment of hPSC-CMs with cardiophysiology closer to human hearts, which will facilitate their applications in preclinical and clinical studies, and provide novel insights into molecular regulation of CM maturation.

人多能干细胞来源的心肌细胞的成熟 项目总结 人多能干细胞来源的心肌细胞(hPSC-CMS)提供了一种新的和生理相关的 有潜力用于体外心脏毒性测试和疾病建模的细胞来源 至于体内心脏发育和再生医学的研究。然而，与小学相比， 人类CMS、hPSC-CMS在结构和功能上都不太成熟，这限制了它们准确地 预测心脏毒性并模拟人类发育和疾病，并可能导致不良事件，如 移植后的心律失常。因此，提高hPSC-CM的成熟度是提高hPSC-CM成熟度的关键 这些细胞的应用。我们和其他小组之前已经证明了有效的CM差异化 可以通过模拟体内心脏发生过程中心脏诱导的分子信号来实现hPSCs的分化。 在我们最近的出版物中，我们还表明，微型组织工程能够可靠地生成 含有高度浓缩的hPSC-CMS的3D心脏球体具有增强的肌节结构成熟。 我们假设，一种多管齐下的、协同的方法结合了组织工程和调节 多个分子信号通路可有效促进hPSC-CM短时间培养成熟 持续时间。在这一假设下，我们的目标是通过提供 细胞具有(1)调节新陈代谢成熟的适当化学信号和(2)合适的环境 提示模拟从胎儿CMS到出生后CMS的转变。我们预计这项研究将导致 建立心脏生理更接近人类心脏的hPSC-CMS将为其应用提供便利 在临床前和临床研究中，并为CM成熟的分子调控提供了新的见解。