Regenerating the Heart with Engineered Human Cardiac Tissue

用工程人体心脏组织再生心脏

基本信息

批准号：
8534814
负责人：
Kareen LK Coulombe
金额：
$ 7.22万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-20 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534814
关键词：
Address Adult Alginates Angiogenic Proteins Apoptosis Area Biocompatible Materials Biological Biomedical Engineering Biophysics Blood Vessels Blood capillaries Blood flow Bromodeoxyuridine Cardiac Cardiac Myocytes Cardiovascular system Cause of Death Cell Cycle Cell Therapy Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemical Stimulation Chemicals Clinical Coronary heart disease Cytokinesis DNA biosynthesis Development Disease Drug Delivery Systems Drug Formulations Echocardiography Electric Stimulation Engineering Engraftment Extracellular Matrix Fibroblast Growth Factor 2 Gene Expression Generations Goals Growth Growth Factor Heart Heart Diseases Heart Transplantation Heart failure Histology Human Human Engineering Hypertrophy Immunohistochemistry Implant In Vitro Individual Infarction Insulin-Like Growth Factor I Kinetics Learning Mechanical Stimulation Mechanics Medical Mentors Methods Microspheres Molds Molecular Profiling Myocardial Myocardial Infarction Myocardium Myosin Heavy Chains Natural regeneration Neonatal Neuregulin 1 Nude Rats Pharmaceutical Preparations Phase Physiological Physiology Plant Roots Property Proteins Public Health Rattus Reporting Research Research Personnel Rho-associated kinase Surface System Therapeutic Tissue Engineering Tissue Grafts Tissues Tracer Vascular Endothelial Growth Factors Vascular blood supply Vascularization Western Blotting arteriole aurora B kinase base beta-Myosin capillary career conditioning controlled release density disorder prevention effective therapy heart function human embryonic stem cell implantation improved in vivo induced pluripotent stem cell inhibitor/antagonist injured innovation new technology novel strategies repaired research study restoration scaffold small molecule stem cell biology success therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): Heart failure after a myocardial infarction is primarily due to death of cardiomyocytes, suggesting that successful cell-based therapies will replace cardiomyocytes to restore heart function. To that end, this proposal focuses on generating large human cardiac grafts using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in engineered cardiac tissue with biomaterial delivery of therapeutic growth factors and small molecule drugs. We have developed scaffold-free engineered cardiac tissue with hiPSC- cardiomyocytes and the extracellular matrix that they secrete. These cardiac tissue "patches" are implanted on the epicardial surface of infarcted hearts, but integration with the host is minimal and improved cardiac function is absent. Therefore, this proposal aims to improve host vascularization of the graft (Aim 1), survival and proliferation of hiPSC-derived cardiomyocytes (Aim 2), and force generation by hiPSC-cardiomyocytes (Aim 3). In Aim 1, we will develop biodegradable alginate microspheres loaded with the angiogenic proteins vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). These will be optimized in vitro and in vivo for controlled protein release and incorporated into cardiac patches for implantation in the infarcted rat heart. In Aim 2, we will use alginate microspheres loaded with insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG-1), and Y27632 (a small molecule inhibitor of Rho-associated kinase) to improve hiPSC- cardiomyocyte survival and proliferation during cardiac patch formation and after implantation. In Aim 3, we use chemical, electrical, and mechanical conditioning to promote hiPSC-cardiomyocyte hypertrophy and contractile strength. The current proposal aims to address deficiencies in cell-based cardiac therapy and is innovative in its approach, using degradable biomaterials for therapeutic protein/drug delivery within engineered cardiac tissue. These immediate research goals will encourage my development as an independent investigator. During the mentored K99 phase, I will learn to fabricate alginate microspheres loaded with proteins and drugs. Integrating controlled-release systems with cardiac tissue engineering will result in a unique niche for my research career. It is my long-term career goal to establish an interdisciplinary cardiovascular bioengineering lab that approaches biological and medical problems with novel technologies in tissue engineering, biomaterials, physiology, biophysics, and stem cell biology.

描述（申请人提供）：心肌梗塞后的心力衰竭主要是由于心肌细胞死亡所致，这表明成功的细胞疗法将取代心肌细胞以恢复心脏功能。为此，该提案的重点是在工程心脏组织中使用人类诱导多能干细胞（hiPSC）衍生的心肌细胞生成大型人类心脏移植物，并通过生物材料输送治疗性生长因子和小分子药物。我们开发了含有 hiPSC 心肌细胞及其分泌的细胞外基质的无支架工程心脏组织。这些心脏组织“补片”被植入梗塞心脏的心外膜表面，但与宿主的整合程度极低，并且无法改善心脏功能。因此，该提案旨在改善移植物的宿主血管化（目标 1）、hiPSC 衍生心肌细胞的存活和增殖（目标 2）以及 hiPSC 心肌细胞的力生成（目标 3）。在目标1中，我们将开发负载血管生成蛋白血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的可生物降解的藻酸盐微球。这些将在体外和体内进行优化，以控制蛋白质释放并纳入心脏贴片中用于植入梗塞的大鼠心脏。在目标 2 中，我们将使用负载胰岛素样生长因子-1 (IGF-1)、神经调节蛋白-1 (NRG-1) 和 Y27632（Rho 相关激酶的小分子抑制剂）的藻酸盐微球来改善 hiPSC-心脏补片形成期间和植入后心肌细胞的存活和增殖。在目标 3 中，我们使用化学、电和机械调节来促进 hiPSC 心肌细胞肥大和收缩强度。目前的提案旨在解决基于细胞的心脏治疗的缺陷，其方法具有创新性，使用可降解的生物材料在工程心脏组织内输送治疗性蛋白质/药物。这些近期的研究目标将鼓励我作为一名独立研究者的发展。在指导的 K99 阶段，我将学习制造负载蛋白质和药物的藻酸盐微球。将控释系统与心脏组织工程相结合将为我的研究生涯带来独特的利基。这是我的长期职业目标是建立一个跨学科的心血管生物工程实验室，利用组织工程、生物材料、生理学、生物物理学和干细胞生物学方面的新技术来解决生物和医学问题。