The role of NPY in stress-induced hematopoiesis

NPY 在应激诱导造血中的作用

• 批准号: 10588226
• 负责人: Pratibha Singh
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588226
• 关键词: Acceleration; Acute; Adrenergic Agents; Applications Grants; Blood; Blood Vessels; Bone Marrow; CSF3 gene; CXCR4 gene; Cell Count; Cell surface; Cells; Chemotherapy and/or radiation; Chronic; Circulation; Collecting Cell; Complication; DNA Damage; Data; Defect; Dipeptidyl-Peptidase IV; Dose; Endogenous Factors; Endothelial Cells; Engraftment; Functional disorder; Generations; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Homing; Human; Immune; Impairment; Inherited; Ionizing radiation; Knockout Mice; Maintenance; Malignant - descriptor; Mediating; Metabolic Diseases; Modeling; Molecular; Mus; Natural regeneration; Neurons; Neuropathy; Neuropeptide Y Receptor; Neurotransmitters; Neutropenia; Non-Malignant; Opportunistic Infections; Outcome; Oxidative Stress; Pathologic; Patients; Peptidyl-Dipeptidase A; Peripheral Nervous System Diseases; Physiological; Play; Population; Premature aging syndrome; Prevention approach; Production; Radiation; Reactive Oxygen Species; Recovery; Regimen; Regulation; Reporting; Risk; Role; Signal Transduction; Stem cell transplant; Stress; Supplementation; System; Testing; Therapeutic; Transplantation; Whole-Body Irradiation; Wild Type Mouse; Work; acquired bone marrow failure; adaptive immunity; alpha-Thalassemia; bone marrow failure syndrome; chemoradiation; chemotherapy; conditioning; cytotoxic; exposed human population; genetic manipulation; genotoxicity; hematopoietic engraftment; hematopoietic stem cell niche; hematopoietic transplantation; improved; irradiation; mesenchymal stromal cell; migration; neuropeptide Y; neuroprotection; neurotransmission; novel therapeutic intervention; pharmacologic; preconditioning; reconstitution; repaired; response; restoration; senescence; stem cell function; stem cell homeostasis; stem cell niche; stem cell survival; therapeutic target; transplant model

ABSTRACT Hematopoietic stem cell (HSC) transplantation is a therapeutic cure for hematological malignancies, metabolic disorders, and inherited and acquired bone marrow (BM) failure. However, myeloablative conditioning regimens routinely used for transplantation cause acute and long-term BM damage, leading to impaired blood and immune cell production, often causing fatal consequences. Although myeloablative irradiation/chemotherapy-induced defects in the BM microenvironment/niche have been reported, the underlying mechanism(s) are not well understood. The other crucial limiting factor for HSC transplantation is an inadequate number/quality of transplantable HSPC collected from patients or donors. Emerging evidence suggests the pivotal role of neuronal signals in the BM niche and HSC function. Peripheral neuropathy is a common complication associated with radiotherapy and chemotherapy. Thus, a deficit of neuronal signals in the BM can impair hematopoietic reconstitution. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters, regulates hematopoietic stem and progenitor cell (HSPC) release into circulation by regulating BM vascular gateway function. Preliminary data showed that steady-state, NPY knockout (KO) mice have fewer HSPC and BM niche endothelial cell (EC) and mesenchymal stromal cell (MSC) than wild-type (WT) mice. Interestingly, total body irradiation (TBI) reduces NPY levels in mouse BM, accompanied by a scarcity of EC and MSC. Furthermore, we found that BM EC and MSC from NPY KO mice produce higher reactive oxygen species (ROS) than WT mice. Also, NPY supplementation enhances HSPC ex vivo expansion. Based on these observations, we hypothesize that NPY is required for BM niche regulation and HSPC homeostasis, and cytotoxic stress- induced deficit of NPY signals in the BM impairs NPY-regulated BM niche extrinsic and HSPC intrinsic mechanisms leading to hematopoietic dysfunction. This hypothesis will be tested in three aims herein: Specific aim 1 will investigate whether myeloablative irradiation-mediated deficit of NPY signals in the BM causes acute and chronic defects in the BM niche and impairs hematopoietic regeneration. Using mouse HSC transplantation models, we will evaluate the relationship between NPY signals and irradiation-induced structural and functional defects in the BM niche and HSPC. Specific aim 2 will identify the mechanism(s) via which NPY signals promote BM niche restoration and hematopoietic regeneration. We will use molecular and functional analysis to explore how NPY signals control oxidative stress and vascular integrity in the BM niche constituents. Specific aim 3 will investigate whether NPY supplementation during ex vivo HSPC expansion can improve hematopoietic engraftment after transplantation. The proposed studies will shed new light on how stress-induced neuropathy contributes to stem cell niche damage and blood stem cell defects and identify a potential therapeutic target to improve HSC transplantation.

摘要 造血干细胞（HSC）移植是一种治疗恶性血液病、代谢性疾病和其他疾病的方法。 疾病以及遗传性和获得性骨髓（BM）衰竭。然而，清髓性预处理方案 常规用于移植会引起急性和长期的BM损伤，导致血液和免疫功能受损， 细胞生产，往往造成致命的后果。尽管清髓性放疗/化疗诱导 已经报道了BM微环境/生态位中的缺陷，但其潜在机制尚不清楚 明白HSC移植的另一个关键限制因素是HSC数量/质量不足。 从患者或供体收集的可移植HSPC。新出现的证据表明，神经元的关键作用， BM龛中的信号和HSC功能。周围神经病变是一种常见的并发症， 放疗和化疗。因此，BM中神经元信号的缺陷可损害造血功能。 重组我们最近报道，神经肽Y（NPY），最丰富的神经递质之一， 通过调节BM血管调节造血干细胞和祖细胞（HSPC）释放到循环中 网关功能初步数据显示，稳态，NPY敲除（KO）小鼠具有较少的HSPC， BM龛内皮细胞（EC）和间充质基质细胞（MSC）比野生型（WT）小鼠。有趣的是， 全身照射（TBI）降低了小鼠BM中的NPY水平，伴随着EC和MSC的缺乏。 此外，我们发现来自NPY KO小鼠的BM EC和MSC产生更高的活性氧（ROS）。 WT小鼠。此外，NPY补充增强HSPC离体扩增。根据这些观察， 我们假设NPY是BM生态位调节和HSPC稳态以及细胞毒性应激所必需的- 在BM中诱导的NPY信号缺陷损害了NPY调节的BM生态位外在和HSPC内在 导致造血功能障碍的机制。本文将在三个目标中检验这一假设： 具体目标1将研究骨髓中清髓性放射介导的NPY信号缺陷是否 引起骨髓龛的急性和慢性缺陷并损害造血再生。使用小鼠HSC 移植模型，我们将评估NPY信号与辐射诱导的结构性损伤之间的关系。 以及BM龛和HSPC中的功能缺陷。 具体目标2将确定NPY信号促进BM生态位恢复的机制， 造血再生我们将使用分子和功能分析来探索NPY信号如何控制 氧化应激和血管完整性的BM生态位成分。 具体目标3将研究在离体HSPC扩增期间补充NPY是否可以改善 移植后造血植入。 这项研究将为压力诱导的神经病变如何促进干细胞生态位提供新的线索 损伤和造血干细胞缺陷，并确定潜在的治疗靶点，以改善造血干细胞移植。