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：
8826171
负责人：
Kareen LK Coulombe
金额：
$ 24.9万
依托单位：
BROWN UNIVERSITY
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826171
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 Geometry 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 abstracting arteriole aurora B kinase base beta-Myosin capillary cardiac regeneration 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

Project Summary/Abstract 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.

项目概要/摘要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，这该提案的重点是利用人类诱导多能干细胞生成大型人类心脏移植物工程化心脏组织中的 (hiPSC) 衍生心肌细胞通过生物材料输送治疗性生长因子和小分子药物。我们开发了带有 hiPSC 的无支架工程心脏组织心肌细胞及其分泌的细胞外基质。这些心脏组织“补片”被植入梗塞心脏的心外膜表面，但与宿主的整合很少，并且改善了心脏功能缺席。因此，该提案旨在改善移植物的宿主血管化（目标 1）、存活率和 hiPSC 衍生的心肌细胞的增殖（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的可生物降解的藻酸盐微球内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）。这些将在体外进行优化以及在体内控制蛋白质释放并掺入心脏贴片中植入梗塞部位老鼠的心。在目标 2 中，我们将使用装载有胰岛素样生长因子-1 (IGF-1) 的藻酸盐微球，神经调节蛋白-1 (NRG-1) 和 Y27632（Rho 相关激酶的小分子抑制剂）可改善 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。当前的提案旨在解决基于细胞的心脏治疗的缺陷，并且是其方法具有创新性，使用可降解生物材料在体内输送治疗性蛋白质/药物工程心脏组织。这些近期的研究目标将鼓励我作为一名独立调查员。在指导K99阶段，我将学习制作海藻酸盐微球富含蛋白质和药物。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了独特的利基。建立一个跨学科的学科是我的长期职业目标心血管生物工程实验室，利用新技术解决生物和医学问题组织工程、生物材料、生理学、生物物理学和干细胞生物学。