Myogenic potential of human embryonic stem cells in heterochronic environments

描述（由申请人提供）：虽然过去几年的许多研究都集中在人胚胎干细胞（hESC）的衍生、繁殖和体外分化上，但与年轻、全身和局部器官环境相反，对hESC在老年人中的自我更新和多能性知之甚少。如果对这些细胞及其后代的治疗希望是有助于老年人的患病组织，但它们的再生能力受到老年环境的不利影响，那么它们的治疗价值就会显著降低。当然，除非与年龄有关的影响干细胞再生能力的变化被理解和抵消。我们的数据强烈表明，老年人的小生境确实有显着的抑制作用，人胚胎干细胞的再生能力和外在的线索调节干细胞的激活成为随着年龄的变化。因此，很可能与年龄相关的系统和器官环境的变化也会阻止移植的hESC或其后代对旧的患病组织进行有效的修复。这项工作将测试hESC再生骨骼肌的能力在很大程度上取决于其外在环境的年龄的特定假设，将定义由其外在生态位的年龄相关改变引起的hESC再生和肌生成潜力的变化，将比较暴露于“年轻”和“老年”的hESC的基因表达谱，环境，并将提供影响衰老组织中干细胞再生潜力的抑制组分的初始分子表征。我们将使用联邦批准的hESC细胞系WA07和UC 06进行这项拟定工作。这些数据将有助于理解局部和系统环境控制年轻与老年生物体中干细胞行为的分子机制。这些研究的结果预计将是至关重要的破译衰老的关键分子决定因素，为了解调节人胚胎干细胞增殖和细胞命运决定的途径，并为提高人胚胎干细胞的治疗价值的背景下，老化的器官和组织。

DESCRIPTION (provided by applicant): While many studies of the past years have focused on the derivation, propagation and in vitro differentiation of human embryonic stem cells (hESC), little is known about the self-renewal and pluripotency of hESC in the aged, as opposed to the young, systemic and local organ environments. If the therapeutic hope for these cells and their progeny is to contribute to the ailing tissues in older individuals, but their regenerative capacity is adversely affected by the aged milieu, then their therapeutic value becomes significantly diminished. Unless, of course, the age-related changes affecting stem cell regenerative capacity are understood and countered. Our data strongly suggest that the aged niche has indeed a pronounced inhibitory influence on the regenerative capacity of hESC and that extrinsic cues regulating activation of stem cells become altered with age. It is, therefore, quite possible that the age-related changes in the systemic and organ environments would also preclude a productive repair of old ailing tissues by the transplanted hESC or their progeny. This work will test the specific hypothesis that the ability of hESC to regenerate skeletal muscle is, to a large extent, dependent on the age of their extrinsic environment, will define the changes in hESC regenerative and myogenic potential that are caused by the age-related alterations of their extrinsic niche, will compare the gene expression profile of hESC exposed to "young" versus "old" milieu and will provide initial molecular characterization of the inhibitory components affecting regenerative potential of stem cells in aged tissues. We will use the Federally approved hESC lines WA07 and UC06 for this proposed work. The data will help to understand the molecular mechanism(s) by which local and systemic environments control behavior of stem cells in young versus old organisms. The outcome of these studies is expected to be fundamentally important for deciphering key molecular determinants of aging, for understanding the pathways regulating hESC proliferation and cell-fate determination, and for enhancing the therapeutic value of hESC in the context of aged organs and tissues.