iPS cells-derived progenitor cells for angiomyogenesis

iPS 细胞衍生的祖细胞用于血管肌生成

• 批准号: 8852679
• 负责人: Muhammad Ashraf
• 金额: $ 71.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852679
• 关键词: Adenylate Cyclase; Adopted; Area; Autologous; Autologous Transplantation; Basic Science; Biomechanics; Blood Vessels; Bone Marrow; Capillary Endothelial Cell; Cardiac; Cardiac Myocytes; Cell Line; Cell Lineage; Cell Survival; Cells; Cicatrix; Coculture Techniques; Coronary artery; Coupled; Data; Deterioration; Development; Down-Regulation; Effectiveness; Endothelial Cells; Engineering; Engraftment; Fibroblasts; Fibrosis; Genes; Genetic; Goals; Growth; Heart failure; Human; Hypoxia; Immune; In Vitro; Infarction; Lead; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Metabolic; MicroRNAs; Modification; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Natural regeneration; Nutrient; Outcome Measure; Pathway interactions; Patients; Performance; Perfusion; Phenotype; Property; Pump; Research; Rodent Model; Smooth Muscle Myocytes; Source; Stem cells; Stretching; Therapeutic; Tissue Engineering; Tissue Grafts; Tissue Viability; Tissues; Vascular Endothelial Cell; Vascular blood supply; Ventricular; Waste Products; adenylyl cyclase 6; artery occlusion; blood vessel development; cardiac repair; coronary fibrosis; density; functional improvement; implantation; improved; in vivo; induced pluripotent stem cell; injured; insight; migration; muscle regeneration; neovascular; neovasculature; novel strategies; overexpression; preconditioning; precursor cell; progenitor; protein expression; repaired; stem cell differentiation

DESCRIPTION (provided by applicant): Various tissue engineering strategies have been adopted to treat damaged heart muscle as a result of myocardial infarction. However, the rebuilt myocardium must include a vascular network able to nourish it under diverse metabolic demands. Recently we demonstrated the efficacy of such an approach using cardiac tissue grafts developed from genetically modified mesenchymal stem cells. While demonstrating the value of such an approach, a better source of cells for tissue engineering would be induced pluripotent stem cells (iPSCs) derived from the patient's own tissues. Our objective is to develop a novel approach to treatment of myocardial infarction (MI), using a rodent model, that involves tissue engineering using iPSCs. Such an approach could eventually be used in humans and would allow autologous transplantation, thereby eliminating the problem of host rejection. The use of iPSCs will allow efficient differentiation into endothelial cells and other cardiac lineage cells, immune compatibility between donor and recipient tissues, and rapid transport of nutrients and waste products to new and developing tissue (via blood vessel formation). We hypothesize that a tri-cell patch composed of a network of iPSC-derived endothelial cells and other cardiac lineage cells will be effective for regrowth of neovasculature and myocardial tissue, which in turn could lead to improved cardiac function. In Aim 1, we will perform in vitro studies to characterize iPSC differentiation and define the optimal conditions for their directed differentiation into endothelial and cardiomyocyte cell lineages that will be suitable for development of a tri-cell patch to be used in cardiac repair. We will further enhance the angiogenic or myogenic potential of cardiac precursor cells, and determine whether preconditioning promotes differentiation of iPSCs into cardiac lineage cells. In Aim 2 we will determine whether a prevascularized cell patch will increase the retention and survival of iPSC-derived cardiac phenotypes after implantation leading to significant improvements in vascularity, perfusion, and cardiac function. Studies in Aim 3 will determine whether downregulation of fibrosis by manipulating subcellular pathways by over expression of adenylyl cyclases or specific fibrosis repressive microRNAs will influence the engraftment of a cardiac progenitor cell patch after myocardial infarction. These studies will provide new insights into the development of engineered iPSC-derived cardiac tissue patches as a viable therapy for cardiac muscle regeneration.

描述（由申请人提供）：已采用各种组织工程策略来治疗因心肌梗塞而受损的心肌。但是，重建的心肌必须包括一个能够在多种代谢需求下滋养其的血管网络。最近，我们证明了使用从转基因间充质干细胞开发的心脏组织移植物的这种方法的功效。在证明这种方法的价值的同时，将引起从患者自身组织的多能干细胞（IPSC）引起的更好的组织工程细胞来源。我们的目标是开发一种使用啮齿动物模型的新型方法来治疗心肌梗死（MI），该模型涉及使用IPSC的组织工程。这种方法最终可以在人类中使用，并允许自体移植，从而消除宿主排斥的问题。 IPSC的使用将有效分化为内皮细胞和其他心脏谱系细胞，供体和受体组织之间的免疫兼容，以及将养分和废物的快速运输到新的和发育中的组织（通过血管形成）。我们假设由IPSC衍生的内皮细胞网络和其他心脏谱系细胞组成的三细胞斑块将有效地进行新生植和心肌组织的再生，这又可以改善心脏功能。在AIM 1中，我们将进行体外研究，以表征IPSC分化，并定义其将其定向分化为内皮和心肌细胞谱系的最佳条件，这些谱系适用于在心脏修复中使用三细胞斑块的开发。我们将进一步增强心脏前体细胞的血管生成或肌原性潜力，并确定预处理是否促进IPSC分化为心脏谱系细胞。在AIM 2中，我们将确定植入后IPSC衍生的心脏表型的保留率和存活是否会导致血管性，灌注和心脏功能的显着改善。 AIM 3中的研究将确定通过过度表达腺苷酸环化酶或特定的纤维化抑制性microRNA会影响心肌梗死后心脏祖细胞斑块的植入而通过操纵亚细胞途径的下调。这些研究将为工程IPSC衍生的心脏组织斑块的发展提供新的见解，作为一种可行的心脏肌肉再生疗法。