Bone marrow NPY deficiency triggers HSC aging

摘要 衰老损害造血干细胞和祖细胞（HSPC）的再生潜力并使HSPC偏斜 向髓系分化。HSPC中的这些缺陷可能导致与衰老相关的血液 疾病，包括对感染的易感性增加，贫血的风险增加，以及骨髓性疾病的易感性， 肿瘤。骨髓（BM）微环境最近被认为影响HSPC老化。 然而，骨髓基质细胞介导HSPC老化的机制还不清楚。我们最近 神经肽Y（neuropeptide Y，NPY）是BM中最丰富的神经递质之一， 微环境，通过控制BM血管门户功能来关键性地调节HSPC运输。在 健康的年轻小鼠，我们和其他的研究表明，神经肽Y遗传缺陷损害BM小生境细胞存活 并减弱遗传毒性应激后的造血恢复。最近有报道，血液中的NPY 在老年人群中水平下降。在初步研究中，我们发现， 并伴有BM巢细胞和HSPC数量的变化。岁 小鼠骨髓间充质干细胞和内皮细胞活性氧（ROS）水平升高 产生，并且NPY缺乏的年轻小鼠显示出BM ROS水平的类似增加。我们还发现， 用NPY体内处理老化的HSPC基本上逆转了老化的HSPC自噬缺陷。基于这些 通过观察，我们假设衰老介导的BM中NPY信号的缺陷损害了关键的 支持BM生态位活性和HSPC功能的内源性机制导致HSPC老化。这 假设将在两个目标中进行测试。具体目标1将研究衰老介导的NPY缺陷是否 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水平并评估BM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/交替有助于 BM微环境和HSPC功能的年龄相关缺陷。我们将评估与衰老有关的 BM NPY的缺乏导致生态位和HSPC衰老标志，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。 拟议的研究将揭示衰老相关的BM NPY信号减少如何有助于BM 生态位交替和造血干细胞缺陷，并确定潜在的治疗靶点，以改善造血 在老年人中恢复活力。

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.