Mesenchymal Stem Cell Therapeutics in Hibernating Myocardium

慢性心肌缺血导致心力衰竭是心脏疾病发病率和死亡率的主要原因。 美国。实验性心肌干细胞治疗已在急性心肌梗死患者中大量实施。 缺血模型。已建立的猪冬眠心肌模型，它与 人类冠状动脉疾病的慢性和稳定性，将被用来开发和优化治疗方法 基于干细胞和基因治疗相结合的策略。骨髓源性猪间充质细胞 体外扩增的干细胞(MSCs)具有强大的自我更新和多向分化能力 潜在的，并能够产生许多生长因子和细胞因子。尽管很有希望成为 再生医学在衰老和疾病中的作用，MSCs有待进一步分析其机制 控制它们的生长、分化、存活、组织归巢和衰老特征。生长因子 骨髓间充质干细胞多系分化潜能的调节、衰老对骨髓间充质干细胞功能的影响及其应用 同种异体骨髓间充质干细胞将被鉴定。这些努力的核心是使用重组腺病毒 表达与细胞保护、血管生成和间充质干细胞归巢相关的基因。提案的第一部分 依赖于MSCs广泛的细胞培养特性，为第二部分奠定了基础 解决工程MSCs的生理效应的提案。目标1将决定差异 多种血管内皮生长因子亚型对猪MSCs生长及多向分化潜能的影响目标2将 分析MSC趋化因子受体在心肌MSC归巢中的表达和调控。 目标3将描述细胞和动物老化对骨髓间充质干细胞生长能力、细胞存活的影响 能力、多系潜能和趋化迁移潜能。目标4将针对以下目标优化战略 心肌内移植间充质干细胞体内去向的示踪及可行性评价 使用同种异体骨髓间充质干细胞和老化的MSCs。AIM 5将确定骨髓间充质干细胞是否为提高存活率而设计 容量、血管生成潜力或归巢潜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。从长远来看，基于MSC的治疗在猪身上的翻译 冬眠心肌和再生药物将用于慢性冠状动脉疾病患者 引领最优化的MSC疗法，在管理衰老和治愈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.