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

基本信息

批准号：
8701393
负责人：
MICHAEL Alan LAFLAMME
金额：
$ 41.69万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8701393
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

项目摘要

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（由申请人提供）：由于多能人胚胎干细胞（hESC）具有巨大的体外扩增能力和分化为表型明确的心肌细胞的能力，因此成为基于细胞的心脏治疗的有吸引力的来源。我们小组获得了令人兴奋的新数据，表明 hESC 衍生的心肌细胞 (hESC-CM) 在移植到豚鼠心脏后可以与宿主心肌偶联，但它们在受伤心脏中的整合并不完美。我们还发现 hESC-CM 移植显着降低自发性和诱发性心律失常的发生率。本申请建立在这些观察的基础上，有两个总体目标：首先，确定这种心律失常抑制作用的机制基础，其次，测试进一步增强受损心脏中 hESC-CM 机电整合的新方法。在目标 1 中，我们将检验以下假设：hESC-CM 移植对电稳定性的有益影响与其功能整合相关。在目标 2 中，我们将测试以下假设：在豚鼠梗塞模型中进行 hESC-CM 移植后，间隙连接修饰剂的治疗将改善宿主与移植物的耦合。最后，在目标 3 中，我们将使用体外模型开发 Wnt5a 介导的趋化性，作为改善 hESC-CM 移植物整合的补充策略。