Mesenchymal Stem Cell Therapeutics in Hibernating Myocardium

冬眠心肌的间充质干细胞治疗

• 批准号: 7201606
• 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/7201606
• 关键词: Acute; Acute myocardial infarction; Address; Adenoviruses; Adult; Age; Aging; Allogenic; Animal Model; Animals; Autologous; Bone Marrow; Cell Lineage; Cell Survival; Cell Therapy; Cells; Cellular biology; Characteristics; Chronic; Clinical; Coronary Arteriosclerosis; Coupled; Critical Pathways; Cultured Cells; 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; Personal Satisfaction; Phenotype; Physiological; Population; 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 therapy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：导致心力衰竭的慢性心肌缺血是美国发病和死亡的主要原因。实验性心肌干细胞疗法主要在急性缺血模型中进行。完善的猪冬眠心肌模型与人类冠状动脉疾病的慢性性和稳定性非常相似，将用于开发和优化基于干细胞和基因联合治疗的治疗策略。培养扩增的骨髓来源的猪间充质干细胞（MSC）具有强大的自我更新和多谱系分化潜力，并且能够产生许多生长因子和细胞因子。尽管间充质干细胞有望作为衰老和疾病的再生医学，但其生长、分化、存活、组织归巢和衰老特征的控制机制仍有待进一步分析。将描述生长因子对 MSC 多谱系潜能的调节、衰老对 MSC 功能的影响以及同种异体 MSC 的使用。这些努力的核心是使用重组腺病毒表达参与细胞保护、血管生成和间充质干细胞归巢的基因。该提案的第一部分依赖于 MSC 的广泛细胞培养特征，为解决工程化 MSC 的生理效应的提案第二部分奠定了基础。目标 1 将确定多种 VEGF 同工型对猪 MSC 的生长和多谱系潜力的不同影响。目标 2 将分析参与心肌 MSC 归巢的 MSC 趋化因子受体的表达和调节。目标 3 将表征细胞和动物衰老对 MSC 生长能力、细胞存活能力、多谱系潜力和趋化迁移能力的影响。目标 4 将优化跟踪和识别心肌中植入 MSC 的体内命运的策略，并评估使用同种异体和老化 MSC 的可行性。目标 5 将确定经过改造以增强存活能力、血管生成潜力或归巢能力的 MSC 是否可以更好地改善慢性冬眠心肌的血流和功能。从长远来看，猪冬眠心肌中基于 MSC 的疗法与人类慢性冠状动脉疾病的再生医学之间的转化将带来优化的 MSC 疗法，在控制衰老和治疗疾病方面具有临床价值。