Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

人多能干细胞源性心肌细胞的成熟 项目摘要 人多能干细胞衍生的心肌细胞（hPSC-CM）提供了一种新的和生理相关的心肌细胞。 具有用于体外心脏毒性测试和疾病建模的潜力的细胞来源 至于体内心脏发育和再生医学的研究。与小学相比， 人CM、hPSC-CM在结构上和功能上较不成熟，这限制了它们准确地表达 预测心脏毒性，模拟人类发育和疾病，并可能导致不良事件，如 移植后心律失常。因此，改善hPSC-CM成熟是至关重要的，以便改善 这些细胞的应用。我们和其他小组先前已经证明，有效的CM分化 可以通过模拟体内心脏发生期间心脏诱导的分子信号传导来实现。 在我们最近的出版物中，我们还表明，微尺度组织工程能够可靠地产生 的3D心脏球体，其含有具有增强的肌节结构成熟的高度富集的hPSC-CM。 我们假设，一种多管齐下的，协同的方法，结合组织工程与调节， 多种分子信号通路可有效促进hPSC-CM在短培养时间内成熟 持续时间。根据这一假设，我们的目标是通过提供以下途径使hPSC-CM能够代谢和功能成熟： 细胞具有（1）调节代谢成熟的适当化学信号和（2）合适的环境条件， 提示模仿从胎儿CM到出生后CM的转变。我们预计，这项研究将导致 建立更接近人体心脏的hPSC-CM，为hPSC-CM的临床应用奠定基础 在临床前和临床研究，并提供新的见解CM成熟的分子调控。

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.