Patterning myocardial specification of human pluripotent stem cells

人类多能干细胞的心肌规格模式化

• 批准号: 10638342
• 负责人: Hee Cheol Cho
• 金额: $ 49.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10638342
• 关键词: Action Potentials; Adrenergic Agents; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiotoxicity; Catecholaminergic Polymorphic Ventricular Tachycardia; Cell Therapy; Cells; Cues; Custom; Data; Defect; Disease; Disease model; Dose; Electrophysiology (science); Embryo; Exhibits; Female; Gene Mutation; Genotype; Goals; Heart; Heart Atrium; Heart Block; Heart failure; Heterogeneity; Hip region structure; Human; In Vitro; Ion Channel; Measurement; Mechanics; Membrane; Methods; Modeling; Muscle Cells; Mutation; Myocardial; Myocardial Infarction; Myocardium; Names; Nodal; Optics; Patients; Pattern; Persons; Phenotype; Population; Problem Solving; Property; Protocols documentation; Rattus; Recurrence; Regulation; Reproducibility; Sample Size; Signal Transduction; Specific qualifier value; System; Tachyarrhythmias; Technology; Testing; Time; Tissue constructs; Treatment-related toxicity; Tretinoin; Ventricular; Ventricular Arrhythmia; Work; base; cardiac regeneration; cell replacement therapy; chronotropic; disease phenotype; drug discovery; human embryonic stem cell; human male; human pluripotent stem cell; in vivo evaluation; induced pluripotent stem cell; male; progenitor; regenerative therapy; stem cell differentiation; transcription factor; translational goal

Project Summary/Abstract Human pluripotent stem cells (hPSCs) originate from either embryonic or transcription factor-induced origins. Under controlled conditions, they recapitulate cardiac development in vitro and give rise to cardiac myocytes of all subtypes. The de novo cardiac myocytes are the best surrogate for human cardiomyocytes for drug discovery, cardiotoxicity screen and cardiac cell replacement therapies. However, present technology for deriving cardiac myocytes from hPSCs has major hurdles to clear toward the stated translational goals. One major problem is heterogeneity; in a given batch, the derived cardiac myocytes are an indiscriminate blend of all major subtypes of cardiomyocytes, i.e., nodal, atrial and ventricular. No cell therapy, toxicity screen and drug discovery can afford to have undefined sub-populations of cardiac myocytes in a dish. We propose to solve this problem by imposing one of the most potent signals during cardiac development on cardiac myocyte patterning during hPSC differentiation. We hypothesize that retinoic acid (RA) signaling steers hPSCs to differentiate toward discrete populations of ventricular or atrial cardiomyocytes of the first heart field. Our preliminary data indicate that temporal and dose dependent manipulation of RA signaling leads to enriched populations of atrial or ventricular cardiomyocytes from hESCs and hiPSCs. Furthermore, the cardiac chamber-specific cardiomyocytes are functionally distinguishable in their electrical excitation and mechanical contraction. We will build on our initial observations to discover a robust and generalizable signaling axis to attain cardiac chamber-specific myocytes with genotypic and phenotypic hallmarks of the native ventricular and atrial myocytes. Successful completion of this proposal will lead to understanding of female vs. male differences in cardiogenic potential of hiPS cells and the fidelity of cardiac chamber-specific disease modeling.

项目概要/摘要 人类多能干细胞 (hPSC) 源自胚胎或转录因子诱导的起源。 在受控条件下，它们在体外重现心脏发育并产生心肌细胞 所有亚型。从头心肌细胞是人类心肌细胞药物的最佳替代品 发现、心脏毒性筛查和心脏细胞替代疗法。然而，目前的技术 从 hPSC 中衍生心肌细胞要实现既定的转化目标还需要克服重大障碍。一 主要问题是异质性；在给定的批次中，衍生的心肌细胞是不加区别的混合物 心肌细胞的所有主要亚型，即结节型、心房型和心室型。无细胞疗法、毒性筛查和 药物发现可以在培养皿中放置未定义的心肌细胞亚群。我们建议 通过在心肌细胞上施加心脏发育过程中最有效的信号之一来解决这个问题 hPSC 分化过程中的模式化。我们假设视黄酸 (RA) 信号传导 hPSC 分化为第一心区的离散的心室或心房心肌细胞群。我们的 初步数据表明，RA 信号传导的时间和剂量依赖性操作可导致丰富的 来自 hESC 和 hiPSC 的心房或心室心肌细胞群。此外，心脏 腔室特异性心肌细胞的电激发和机械作用在功能上是可区分的 收缩。我们将在初步观察的基础上发现一个强大且可推广的信号轴 获得具有天然心室和表型特征的心室特异性肌细胞 心房肌细胞。成功完成该提案将有助于理解女性与男性 hiPS 细胞心源性潜力的差异以及心室特异性疾病模型的保真度。

项目成果

Spotlight on recent advances in cardiovascular biology.

聚焦心血管生物学的最新进展。

• 发表时间: 2019
• 影响因子: 12.8
• 作者: Kook, Hyun;Cho, Hee Cheol
• 通讯作者: Cho, Hee Cheol

Methodology for Cross-Talk Elimination in Simultaneous Voltage and Calcium Optical Mapping Measurements With Semasbestic Wavelengths.

使用声磁波长同时进行电压和钙光学映射测量中串扰消除的方法。

• 发表时间: 2022
• 作者: Uzelac, Ilija;Crowley, Christopher J;Iravanian, Shahriar;Kim, Tae Yun;Cho, Hee Cheol;Fenton, Flavio H
• 通讯作者: Fenton, Flavio H