Preserving bone marrow niche integrity and function to rejuvenate aged hematopoietic stem cells

项目摘要 衰老过程与治疗造血干细胞疾病的治疗策略失败的风险增加有关。 造血干细胞（HSC）移植是造血干细胞治疗的一种有效方法。那里 是开发预防和治疗选择以延缓衰老过程的实质性需求， 使组织/器官恢复活力，并增强再生和修复。然而，真正使老年人恢复活力的能力 HSC或其支持性利基一直困扰着科学家。迄今为止，已发表的返老还童研究表明， 老年HSC功能的几个方面有轻微改善，并夸大了“HSC”的说法。 在不使用分析来严格评估老化干细胞的情况下，这项研究揭示了 Netrin-1（NTN 1）作为一种小生境衍生的信号，可用作一种治疗剂，可以恢复神经元的功能， 老化的HSC，包括其自我更新能力，通过重新激活DNA损伤反应（DDR）途径 以及解决DNA损伤，这是衰老造血系统的标志性特征。我们进一步将NTN 1定义为 HSC生态位功能的关键调节因子，其中在关键骨髓（BM）生态位成分中NTN 1的缺失 导致血管完整性和间充质干细胞功能下降。本提案将阐明 BM小生境的老化导致HSC功能下降的细胞和分子机制， 并验证Netrin-1作为一种新的治疗靶点，其输注可以增强，保护和恢复活力， 衰老的造血系统具体来说，我们将：1）确定哪些HSC特异性和BM利基特异性 NTN 1受体对于再生老化的造血系统至关重要，2）确定NTN 1治疗是否可以 预防或延缓衰老过程，以促进造血健康和长寿，3）发现 由NTN 1信号调节的细胞相互作用和分子机制， HSC和BM龛细胞内的DDR通路，以及4）测试体内输注NTN 1是否可以增强HSC和BM龛细胞内的DDR通路。 骨髓抑制后老化BM微环境的再生。我们的研究计划将利用 创新的体内动物模型和成像技术，以确定我们是否可以减轻衰老相关的 通过增强NTN 1信号传导在老年个体中观察到的病理性造血表型。使用 通过复杂的动物模型，我们将确定细胞中NTN 1及其受体的关键细胞来源， 在衰老过程中保持HSC和生态位功能所需的特定方式。的成功 这项研究计划将为开发一系列广泛的治疗策略开辟新的途径 旨在有效地逆转与年龄相关的造血缺陷。

PROJECT SUMMARY The aging process is associated with an increased risk of failure of therapeutic strategies to treat hematopoietic diseases, which often rely on myelosuppression and transplantation of hematopoietic stem cells (HSCs). There is a substantial need for the development of preventative and therapeutic options to delay the aging process, to rejuvenate tissues/organs, and to enhance regeneration and repair. However, the ability to truly rejuvenate aged HSCs or their supportive niches has eluded scientists. To date, published rejuvenation studies have shown marginal improvements in a few aspects of aged HSC function and have made exaggerated claims of `HSC rejuvenation' without employing assays to stringently evaluate aged stem cells. This research proposal reveals Netrin-1 (NTN1) as a niche-derived signal that can be utilized as a therapeutic that can restore the function of an aged HSC, including its self-renewal capabilities, by reactivating DNA Damage Response (DDR) pathways and resolving DNA damage, a hallmark feature of the aging hematopoietic system. We further define NTN1 as a critical regulator of HSC niche function, where deletion of NTN1 in critical bone marrow (BM) niche constituents leads to a decrease in vascular integrity and mesenchymal stem cell function. This proposal will elucidate the cellular and molecular mechanisms by which aging of the BM niche contributes to the decline of HSC function, as well as validate Netrin-1 as a new therapeutic target whose infusion can enhance, preserve, and rejuvenate an aging hematopoietic system. Specifically, we will: 1) determine which HSC-specific and BM niche-specific NTN1 receptors are critical for rejuvenating the aged hematopoietic system, 2) determine if NTN1 treatment can prevent or temporize the aging process to promote hematopoietic health span and longevity, 3) discover the cellular interactions and molecular mechanisms regulated by NTN1 signaling that are responsible for activating DDR pathways within HSCs and BM niche cells, and 4) test whether in vivo infusion of NTN1 can enhance the regeneration of an aged BM microenvironment following myelosuppression. Our research plan will utilize innovative in vivo animal models and imaging techniques to determine if we can alleviate aging-related pathological hematopoietic phenotypes observed in aged individuals by enhancing NTN1 signaling. Using sophisticated animal models, we will determine the critical cellular sources of NTN1 and its receptors in a cell- specific manner that are required to preserve HSC and niche function during the aging process. The success of this research proposal will open up new avenues for the development of a wide array of therapeutic strategies designed to effectively reverse age-related hematopoietic deficiencies.