Myogenic potential of human embryonic stem cells in heterochronic environments

描述(申请人提供)：尽管过去几年的许多研究都集中在人类胚胎干细胞(HESC)的来源、增殖和体外分化方面，但对hESC在老年人中的自我更新和多能性知之甚少，而不是年轻的、全身的和局部的器官环境。如果这些细胞及其后代的治疗希望是为老年人患病的组织做出贡献，但它们的再生能力受到老化环境的不利影响，那么它们的治疗价值就会显著降低。当然，除非与年龄相关的影响干细胞再生能力的变化得到了理解和应对。我们的数据有力地表明，老化的生态位确实对hESC的再生能力有明显的抑制影响，并且调控干细胞激活的外部线索随着年龄的增长而改变。因此，与年龄相关的系统和器官环境的变化也很可能会阻止移植的hESC或其后代对陈旧的患病组织进行有效的修复。这项工作将检验特定的假设，即人胚胎干细胞再生骨骼肌的能力在很大程度上取决于其外部环境的年龄，将定义由于其外部生态位年龄相关的改变而导致的人胚胎干细胞再生和生肌潜能的变化，将比较暴露在“年轻”和“老年”环境中的人胚胎干细胞的基因表达谱，并将提供影响衰老组织中干细胞再生潜力的抑制成分的初步分子表征。我们将使用联邦批准的hESC线路WA07和UC06进行这项拟议的工作。这些数据将有助于理解分子机制(S)，通过该机制，局部和系统环境控制年轻和老年生物体中干细胞的行为。这些研究的结果有望对破译衰老的关键分子决定因素、了解调控hESC增殖和细胞命运的途径以及提高hESC在衰老器官和组织中的治疗价值具有重要意义。

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.