Mesenchymal Stem Cell Therapeutics in Hibernating Myocardium

冬眠心肌的间充质干细胞治疗

• 批准号: 7579152
• 负责人: TECHUNG LEE
• 金额: $ 38.48万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579152
• 关键词: Acute; Acute myocardial infarction; Address; Adenoviruses; Adult; Age; Aging; Allogenic; Animal Model; Animals; Autologous; Bone Marrow; Cell Culture Techniques; Cell Lineage; Cell Survival; Cell Therapy; Cells; Characteristics; Chronic; Clinical; Coronary Arteriosclerosis; Coupled; Critical Pathways; Cytoprotection; Data; Differentiation and Growth; Disease; Elderly; Elements; Engineering; Engraftment; Family suidae; Foundations; Future; Generations; Genes; Genetic; Genetic Engineering; Growth; Growth Factor; Heart failure; Homing; Human; Hypoxia; Immunologics; Implant; Inflammatory; Injury; Ischemia; Lead; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardium; Natural regeneration; Outcome; Phenotype; Physiological; Production; Property; Protein Isoforms; Recombinants; Regenerative Medicine; Regulation; Research Personnel; Signal Transduction; Stem cells; Therapeutic; Tissue Differentiation; Tissue Engineering; Tissue Survival; Tissues; Translations; United States; Vascular Endothelial Growth Factors; adult stem cell; aged; angiogenesis; base; cell growth; cell type; cellular engineering; chemokine receptor; cytokine; functional improvement; gene therapy; immunogenic; implantation; improved; in vivo; interstitial; mortality; pre-clinical; programs; response; self-renewal; stem cell biology; stem cell population; stem cell therapy

Chronic myocardial ischemia leading to heart failure is a leading cause of morbidity and mortality in the United States. Experimental myocardial stem cell therapeutics have been performed largely in the acute ischemia model. The well established porcine hibernating myocardium model, which closely resembles the chronicity and stability of human coronary artery disease, will be used to develop and optimize therapeutic strategies based on combined stem cell and gene therapy. Bone marrow-derived porcine mesenchymal stem cells (MSCs) expanded in culture possess robust self-renewal and multilineage differentiation potentials, and are capable of producing many growth factors and cytokines. Although promising as regenerative medicine in aging and disease, MSCs await further analysis regarding the mechanisms governing their growth, differentiation, survival, tissue homing, and aging characteristics. Growth factor modulation of MSC multilineage potential, the influence of aging on the function of MSCs, and the use of allogeneic MSCs will be characterized. Central to these efforts is the use of recombinant adenovirus expressing genes involved in cytoprotection, angiogenesis, and MSC homing. The first part of the proposal relies on extensive cell culture characterizations of MSCs, building the foundation for the second part of the proposal that addresses the physiological effect of engineered MSCs. Aim 1 will determine the differential effects of multiple VEGF isoforms on the growth and multilineage potentials of porcine MSCs. Aim 2 will analyze the expression and regulation of MSC chemokine receptors involved in myocardial MSC homing. Aim 3 will characterize the influence of cellular and animal aging on MSC growth capability, cell survival capacity, multilineage potential, and chemotactic migratory potency. Aim 4 will optimize strategies for tracking and identifying the in vivo fate of implanted MSCs in the myocardium and evaluate the feasibility of using allogeneic and aged MSCs. Aim 5 will determine whether MSCs engineered for enhanced survival capacity, angiogenic potential, or homing potency can better improve flow and function in chronic hibernating myocardium. Long term, the translation between the MSC-based therapy in the porcine hibernating myocardium and regenerative medicine for humans with chronic coronary artery disease will lead to optimized MSC therapeutics that can be of clinical value in managing aging and curing disease.

慢性心肌缺血导致的心力衰竭是美国心脏病发病率和死亡率的主要原因