Role of LINC-mediated Mechanosignaling in MSC Aging

项目摘要 骨髓中的间充质干细胞（MSC）提供骨再生能力， 在承重部位加固骨架。当我们年老或长期卧床时，MSC失去了它们的功能。 再生潜力，通常通过其增殖和分化能力来衡量。MSC的损失 健康导致骨质疏松症和延迟愈合，最终导致生活质量下降， 增加了医疗费用。一个基本的知识差距，阻止有效的治疗衰老和MSC 相关的再生医学是如何老化和卧床不起妨碍MSC的健康。 细胞核是所有细胞活动的中心，它既依赖于机械输入，也依赖于其分子 - 调节最终决定细胞功能的核内染色质组织的转换器， 命运因此，如果不能将这些信息传递到细胞核， 流程.在这里，我们要问的是，衰老是否是一个最终限制信息流入细胞核的过程， 削弱其组织能力和对外部刺激的反应能力。正如我们将展示的，禁用 通过核骨架的连接体促进细胞骨架和核之间的机械连接， 核骨架（LINC）复合物通过影响β连环蛋白和雅普/TAZ来损害机械敏感性 信号这导致间充质干细胞的增殖和分化减少。 我们的主要假设是LINC连接的丧失通过以下方式显著促进MSC老化： 破坏核机械传导。 通过响应[PA 16 -442] -蜂窝结构变更提交的本修订版 在老化期间（R 01），我们将通过两个具体目标来解决我们的主要假设，每个目标都使用 不同的假设，以检查如何抑制LINC复杂的功能，以及如何老化相关的损失 LINC复合物的存在限制了已知的机械转导子β连环蛋白和雅普/TAZ的MSC机械信号传导。 我们将进一步确定力诱导机制如何持续的体力活动保护LINC 复杂的表达，以增加MSC和骨机械信号在老化的背景下。 如果成功的话，我们将首次建立一个关于LINC复合体丢失的机制性理解。 驱动器在老化中降低机械感觉能力。这些目标的实现将提供研究 社区（1）基于LIV的再生方式的疗效，改善LINC介导的 机械信号和（2）健康和老化干细胞的基础结构-功能关系数据 细胞

Project Summary Mesenchymal stem cells (MSC) in bone marrow provide regenerative capacity for bone, replacing and reinforcing the skeleton at load bearing sites. When we age or in prolonged bedrest, MSCs lose their regenerative potential, often measured by their proliferative and differentiation capacity. This loss of MSC health causes osteoporosis and delayed healing, ultimately resulting in decreased quality of life and increased medical costs. A fundamental knowledge gap preventing effective therapies in aging and MSC related regenerative medicine is how aging and bedrest impedes MSC health. The nucleus, central to all cellular activity, relies on both mechanical input as well as its molecular transducers to regulate intra-nuclear chromatin organization that ultimately determine cell function and fate. Thus, failure to transmit this information to the nucleus would lead to the breakdown of these processes. Here, we ask if aging is a process that limits information flow into the nucleus, ultimately diminishing its organizational capacity and responsiveness to outside stimuli. As we will show, disabling the mechanical connection between cytoskeleton and nucleus facilitated by Linker of Nucleoskeleton and Nucleoskeleton (LINC) complexes, impairs mechanosensitivity by affecting βcatenin and YAP/TAZ signaling. This leads to decreased proliferation and differentiation of mesenchymal stem cells. Our principal hypothesis is that loss of LINC-connectivity significantly contributes to MSC aging by disrupting nuclear mechanotransduction. Through this revision submitted in response to [PA16-442] - Changes in Cellular Architecture During Aging (R01), we will address our principal hypothesis through two specific aims, each using a distinct hypotheses to examine how inhibiting LINC complex function as well as how aging related loss of LINC complex limits MSC mechanosignaling of known mechanotransducers βcatenin and YAP/TAZ. We will further determine the force-induced mechanisms of how sustained physical activity protects LINC complex expression to augment MSC and bone mechanosignaling within the context of aging. If successful, we will establish, for the first time, a mechanistic understanding of how loss of LINC complex drives decreased mechanosensory capability in aging. Completion of these aims will provide research communities with (1) efficacy of LIV based regenerative modalities that improve LINC-mediated mechanosignaling and (2) foundational structure-function relationship data in healthy and aged stem cells.