Integration and Arrhythmia Suppression with hESC-Derived Cardiomyocyte Grafts

hESC 来源的心肌细胞移植物的整合和心律失常抑制

• 批准号: 8477849
• 负责人: MICHAEL Alan LAFLAMME
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477849
• 关键词: 3-Dimensional; Acidosis; Action Potentials; Acute; Address; Adult; Anti-Arrhythmia Agents; Arrhythmia; Biological Assay; Cardiac; Cardiac Myocytes; Cause of Death; Cavia; Cell Therapy; Cell Transplantation; Cells; Chemotactic Factors; Chemotaxis; Chronic; Cicatrix; Clinical; Connexin 43; Connexins; Contracts; Coupled; Coupling; Data; Electric Stimulation; Electrocardiogram; Exhibits; Fluorescence; Gap Junctions; Generations; Goals; Heart; Hydrogels; Image; In Vitro; Incidence; Infarction; Left; Ligands; Mechanical Stress; Mediating; Methods; Microfluidics; Microspheres; Modeling; Muscle; Muscle Cells; Myocardial Infarction; Myocardium; Optics; Outcome; Paracrine Communication; Pathway interactions; Peptides; Pharmaceutical Preparations; Phosphorylation; Predisposition; Protein Dephosphorylation; Protocols documentation; Rattus; Reporting; Signal Transduction; Solutions; Source; Stem cell transplant; Stem cells; System; Testing; Tissues; Transplantation; Uncertainty; Ventricular; Water; Work; base; controlled release; efficacy testing; human embryonic stem cell; improved; in vitro Model; in vivo; injured; insight; intercellular communication; intravital imaging; migration; novel strategies; prevent; programs; public health relevance; research study; response; sensor; two-dimensional; voltage

DESCRIPTION (provided by applicant): Because of their tremendous capacity for in vitro expansion and ability to differentiate into phenotypically unambiguous cardiomyocytes, pluripotent human embryonic stem cells (hESCs) are an attractive source for cell-based cardiac therapies. Our group has exciting new data indicating that hESC-derived cardiomyocytes (hESC-CMs) can couple with host myocardium following transplantation in guinea pig hearts, but their integration is imperfect in injured hearts. We have also found that hESC-CM transplantation significantly decreases the incidence of both spontaneous and induced arrhythmias. The present application builds on these observations and has two overall goals: first, to determine the mechanistic basis for this arrhythmia-suppressive effect and, second, to test novel approaches to further enhance the electromechanical integration of hESC-CMs in injured hearts. In Aim 1, we will test the hypothesis that the beneficial effects of hESC-CM transplantation on electrical stability correlates with their functional incorporation. In Aim 2, w will test the hypothesis that treatment with gap-junction modifiers will improve host-graft coupling following hESC-CM transplantation in a guinea pig infarct model. Finally, in Aim 3, we will use in vitro models to develop Wnt5a-mediated chemotaxis as a complementary strategy to improve the integration of hESC-CM grafts.

描述(申请人提供)：由于其巨大的体外扩增能力和分化为明确的心肌细胞的能力，多潜能的人胚胎干细胞(HESCs)是基于细胞的心脏治疗的一个有吸引力的来源。本课题组有令人振奋的新数据表明，人胚胎干细胞来源的心肌细胞(hESC-CMS)在豚鼠心脏移植后可以与宿主心肌偶联，但在损伤心脏中它们的整合还不完善。我们还发现，hESC-CM移植显著降低了自发性和诱发性心律失常的发生率。目前的应用建立在这些观察的基础上，并有两个总体目标：第一，确定这种心律失常抑制作用的机制基础；第二，测试进一步增强受损心脏中hESC-CMS的机电整合的新方法。在目标1中，我们将检验这样一个假设，即hESC-CM移植对电稳定性的有利影响与它们的功能整合有关。在目标2中，我们将在豚鼠脑梗塞模型中检验缝隙连接修饰剂治疗将改善hESC-CM移植后宿主-移植物偶联的假设。最后，在目标3中，我们将使用体外模型来开发Wnt5a介导的趋化作用，作为补充策略来提高hESC-CM移植物的整合。