Bone marrow NPY deficiency triggers HSC aging

摘要 增龄损害造血干/祖细胞(HSPC)的再生能力并使HSPC倾斜 向髓系分化。HSPC的这些缺陷可能与衰老相关的血液有关 疾病，包括对感染的易感性增加，贫血风险增加，以及易患髓系白血病 肿瘤。近来，骨髓微环境被认为是影响HSPC老化的因素。 然而，骨髓基质细胞介导HSPC衰老的机制尚不清楚。我们最近 据报道，神经肽Y(NPY)是骨髓中释放最丰富的神经递质之一 微环境，通过控制骨髓的血管通道功能，对HSPC的运输起关键的调节作用。在……里面 健康的幼鼠、Our和其他研究表明NPY基因缺陷损害了BM壁龛细胞的存活 并延缓基因毒性应激后的造血恢复。最近有报道称，血液中的NPY 在老年人口中，这一水平下降。在初步研究中，我们发现NPY水平降低 老年小鼠骨髓细胞数量和HSPC数量的改变。老态 小鼠骨髓间充质细胞和血管内皮细胞的ROS升高 生产，和NPY缺乏的幼鼠表现出类似的增加骨髓ROS水平。我们还发现前男友 NPY显著逆转老年HSPC自噬缺陷的体内治疗。基于这些 观察到，我们假设BM中NPY信号的老化介导的缺陷损害了关键的 支持BM生态位活动和HSPC功能的内源性机制导致HSPC老化。这 假设将在两个目标上进行检验。具体目标1将调查衰老介导的NPY缺陷 BM中的信号有助于生态位交替和HSPC缺陷。我们将使用遗传学和药理学 调节小鼠模型中NPY水平的方法及评估骨髓生态位和HSPC老化的方法 表型。在具体目标2中，我们将确定NPY缺陷/更替促成的机制(S 骨髓微环境和HSPC功能的增龄性缺陷。我们将评估与衰老相关的 BM NPY缺乏导致NICE和HSPC老化特征，如氧化应激、自噬 损伤和衰老，并确定参与这些过程的转录组途径。 拟议的研究将为BM NPY信号与衰老相关的减少如何促进BM提供新的线索 小生境改变与血液干细胞缺陷和寻找改善造血的潜在治疗靶点 老年人的返老还童。

ABSTRACT Aging impairs the regenerative potential of hematopoietic stem and progenitor cells (HSPC) and skews HSPC differentiation towards the myeloid lineage. These defects in HSPC likely contribute to aging-related blood disorders, including increased susceptibility to infection, increased risk of anemia, and predisposition to myeloid neoplasms. The bone marrow (BM) microenvironment has recently been suggested to influence HSPC aging. However, the mechanisms whereby BM stromal cells mediate HSPC aging are not well understood. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters releases in the BM microenvironment, critically regulates HSPC trafficking by controlling the BM vascular gateway function. In healthy young mice, our and other studies have shown that NPY genetic deficiency impairs BM niche cell survival and attenuates hematopoietic recovery after genotoxic stress. It has recently been reported that blood NPY levels decrease in the elderly human population. In preliminary studies, we have found that NPY levels reduced in the BM of aged mice and were accompanied by the alternation in BM niche cell and HSPC numbers. Aged mice BM niche mesenchymal stromal cell and endothelial cell showed increased reactive oxygen species (ROS) production, and NPY deficient young mice showed a similar increase in BM ROS levels. We also found that ex vivo treatment of aged HSPC with NPY substantially reverted aged HSPC autophagy defect. Based on these observations, we hypothesize that the aging mediated deficit of NPY signals in the BM impairs the crucial endogenous mechanisms that support BM niche activities and HSPC function leading to HSPC aging. This hypothesis will be tested in two Aims. Specific Aim 1 will investigate whether the aging-mediated deficit of NPY signals in the BM contributes to niche alternation and HSPC defects. We will use genetic and pharmacologic approaches to modulate the NPY levels in the mouse models and evaluate BM niche and HSPC aging phenotypes. In Specific Aim 2, we will identify the mechanism (s) by which NPY deficit/alternation contributes to age-related defects in the BM microenvironment and HSPC function. We will evaluate how aging-related deficiency in BM NPY contributes to niche and HSPC aging hallmarks, such as oxidative stress, autophagy impairment, and senescence, and identify the transcriptome pathways involved in these processes. The proposed studies will shed new light on how aging-related reduction in BM NPY signals contributes to BM niche alternation and blood stem cell defects and identify a potential therapeutic target to improve hematopoietic rejuvenation in elderly individuals.