Regenerating the Heart with Engineered Human Cardiac Tissue

用工程人体心脏组织再生心脏

• 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
• 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

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.

项目摘要/摘要 心肌梗死后的心力衰竭主要是由于心肌细胞的死亡，这表明 成功的基于细胞的疗法将取代心肌细胞来恢复心脏功能。为此，这 建议重点是使用人类诱导的多能干细胞来生成大型人类心脏移植物 具有治疗性生长生物材料的工程化心肌组织中(HiPSC)来源的心肌细胞 因子和小分子药物。我们已经开发出无支架的工程化心脏组织，具有HiPSC- 心肌细胞及其分泌的细胞外基质。这些心脏组织“贴片”被植入 梗塞心脏的心外膜表面，但与宿主的整合微乎其微，改善了心功能 缺席了。因此，这项建议旨在改善移植物的宿主血管化(目标1)、存活和 HiPSC来源的心肌细胞的增殖(目标2)，以及由HiPSC-心肌细胞产生的力量(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。 血管内皮细胞生长因子(VEGF)和碱性成纤维细胞生长因子(BFGF)。这些将在体外进行优化。 体内用于受控蛋白释放，并被整合到心脏补片中用于植入梗死灶 老鼠心。在目标2中，我们将使用负载胰岛素样生长因子-1(IGF-1)的海藻酸盐微球， NeuRegin-1(NRG-1)和Y27632(一种Rho相关激酶的小分子抑制剂)改善HiPSC-1 心肌细胞在心脏补片形成和植入后的存活和增殖。在目标3中，我们 使用化学、电气和机械条件处理促进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疗法的不足，并 创新的方法，使用可降解的生物材料治疗蛋白质/药物输送 人造心脏组织。这些迫在眉睫的研究目标将鼓励我作为一个 独立调查员。在指导的K99阶段，我将学习如何制造藻酸盐微球 富含蛋白质和药物。将控释系统与心脏组织工程相结合将 为我的研究事业带来了独特的利基市场。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，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。