Microgravity as model for immunological senescence and its impact on tissue stem cells and regeneration

项目摘要 衰老与免疫反应的失调有关，这也被称为“免疫衰老”。 免疫系统的每个部分都在一定程度上受到衰老过程的影响。然而，适应性免疫 似乎受到更广泛的影响，尤其是T细胞被改变。事实上，数字和 晚期分化T细胞的比例，特别是CD 8 + T细胞，在老年人中高于年轻人， 它们的积累可能有助于增强老年人常见的全身促炎环境 个体有趣的是，CD 8+效应记忆RA（TEMRA）细胞的比例随着CD 8 + T细胞的增加而显著增加。 年龄，这是没有看到的CD 4+细胞。我们不知道究竟是什么导致了这些观察到的变化，但 对可能原因的了解现在开始出现。太空飞行会导致一系列负面健康状况 这种效应可能与免疫衰老相当，免疫衰老似乎是再生的关键调节因子。 组织和器官特异性干细胞的能力器官特异性干细胞和祖细胞可能允许这种设计 器官再生的策略。本提案的总体目标是更好地了解 免疫衰老对组织特异性干细胞再生能力的影响。具体地说， 研究检查骨愈合（通过间充质基质细胞）和血管再生（通过 内皮祖细胞）使用芯片上的组织模拟物来表示“半3D”结构。 最终，我们将使用微重力作为衰老模型，我们将把这些发现转化为改善人类健康的方法。 通过在国际空间站上使用组织芯片长达一个月的时间，值得注意的是，拟议的研究调查 使用组织学分析结合功能和基因组分析的组织芯片的飞行后恢复。在 与空间技术和高级研究系统公司合作。- STaARS，精通 为了维持航天中的细胞培养实验，我们正在建立一个体外组织芯片平台 模拟人体生理学来研究免疫衰老对组织特异性干细胞的影响。这 该系统将被设计用于UH 3阶段的极端空间环境。在UG 3阶段，我们 将检查模拟微重力和正常（1xg）条件对CD 8 + T细胞体外培养的影响 以及它们与干细胞的共培养（UG 3 Aim 1）。在UG 3 Aim 2中，我们将研究微重力的影响 在国际空间站-国家实验室（ISS-NL）对CD 8 + T细胞和干细胞的体外共培养进行了研究。 在UH 3阶段，我们将确定微重力对免疫衰老（CD 8 + T细胞分化）的影响。 细胞转化为TEMRA细胞）和组织特异性干细胞在太空中作为使用微阵列的衰老模型（UH 3 Aim 1）。 最后，在UH 3 Aim 2中，我们将研究组织芯片的飞行后恢复（从Aim 1，UH 3阶段），使用 干细胞的功能分析这一建议将大大有助于我们了解一个 老化的免疫系统对组织愈合和再生的影响。

PROJECT SUMMARY Aging is associated with dysregulation of the immune response, which is also termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected, and it is especially the T cells that are altered. In fact, the number and proportion of late-differentiated T cells, particularly CD8+ T cells, is higher in the elderly than in the young and their accumulation may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in elderly individuals. Interestingly, the proportion of CD8+ effector memory RA (TEMRA) cells increases significantly with age, which is not seen for CD4+ cells. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. Spaceflight causes a suite of negative health effects that may be comparable to immunosenescence, which seems to be a key regulator of the regenerative capacity of tissue- and organ-specific stem cells. Organ-specific stem and progenitor cells may allow the design of strategies for organ regeneration. The overarching objective of this proposal is to gain a better understanding of the influence of immunosenescence on the regenerative capacity of tissue-specific stem cells. Specifically, studies examining the effects of bone healing (by mesenchymal stromal cells) and vascular regeneration (by endothelial progenitor cells) are planned using tissue mimics on chip to represent “semi-3D” architectures. Ultimately, we will use microgravity as an aging model, and we will translate those findings to improve human health on Earth by using tissue chips on the ISS for up to a month. Notably, the proposed studies investigate post-flight recovery of tissue chips using histological analysis combined with functional and genomic analysis. In collaboration with Space Technology and Advanced Research Systems, Inc. - STaARS, well-versed in maintenance of cell culture experiments in spaceflight, we are establishing an in vitro tissue-on-chip platform that mimics human physiology to study the effect of immunosenescence on tissue-specific stem cells. This system will be designed for use in the UH3 phase in the extreme environment of space. In the UG3 phase, we will examine the effect of simulated microgravity and normal (1xg) conditions on in vitro cultures of CD8+ T cells and on their co-culture with stem cells (UG3 Aim 1). In UG3 Aim 2 we will investigate the effect of microgravity at the International Space Station – National Lab (ISS-NL) on in vitro co-cultures of CD8+ T cells and stem cells. In the UH3 phase, we will determine the effect of microgravity on immunosenescence (differentiation of CD8+ T cells into TEMRA cells) and tissue-specific stem cells in space as model for aging using microarrays (UH3 Aim 1). Finally, in UH3 Aim 2, we will investigate post-flight recovery of tissue chips (from Aim 1, UH3 phase) using functional analysis of stem cells. This proposal will contribute materially to our understanding of the impact of an aged immune system on tissue healing and regeneration.