Mesenchymal Stem Cell Therapeutics in Hibernating Myocardium

导致心力衰竭的慢性心肌缺血是老年人发病率和死亡率的主要原因。 美国的实验性心肌干细胞治疗主要在急性 缺血模型建立的猪冬眠心肌模型， 人类冠状动脉疾病的慢性和稳定性，将用于开发和优化治疗 基于干细胞和基因联合治疗的策略。猪骨髓间充质 在培养中扩增的干细胞（MSC）具有稳健的自我更新和多谱系分化 具有多种生长因子和细胞因子。虽然前景看好， 再生医学在衰老和疾病中的作用，MSC等待进一步的机制分析 控制它们的生长、分化、存活、组织归巢和老化特性。生长因子 MSC多谱系潜能的调节、衰老对MSC功能的影响以及MSC的用途。 将表征同种异体MSC。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MSC归巢的基因。建议的第一部分 依赖于广泛的细胞培养表征的间充质干细胞，建立基础的第二部分， 该提案解决了工程化MSC的生理效应。目标1将决定差异 多种VEGF异构体对猪MSCs生长和多向分化潜能的影响。目标2将 分析心肌MSC归巢过程中MSC趋化因子受体的表达及调控。 目的3将表征细胞和动物老化对MSC生长能力、细胞存活和细胞增殖的影响。 能力、多谱系潜能和趋化迁移潜能。目标4将优化战略， 追踪和鉴定心肌中植入的MSC的体内命运，并评估 使用同种异体和老化的MSC。目标5将确定是否MSC工程增强生存 血管生成能力或归巢能力可以更好地改善慢性阻塞性肺疾病患者的血流和功能。 冬眠心肌长期而言，猪中基于MSC的治疗 冬眠心肌和慢性冠状动脉疾病患者再生医学将 导致优化的MSC疗法，其在控制衰老和治疗疾病方面具有临床价值。

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.