The Role of CCL5 in Hematopoietic Stem Cell Activation and Skewing

CCL5 在造血干细胞激活和倾斜中的作用

• 批准号: 10348737
• 负责人: Kellie Rae Machlus
• 金额: $ 13.28万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348737
• 关键词: Activity Cycles; Acute; Address; Affect; Automobile Driving; Biology; Blood Platelets; Cell Cycle; Clinical Data; Colitis; Data; Development; Disease; Disease model; Emergency Situation; Goals; Health; Hematopoiesis; Hematopoietic stem cells; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Knowledge; Lead; Ligands; MPL gene; Mediating; Mediator of activation protein; Megakaryocytes; Megakaryocytopoieses; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mucositis; Mucous Membrane; Mus; Nature; Pathway interactions; Patients; Plasma; Platelet Count measurement; Play; Population; Process; Production; Proteins; Publishing; RANTES; Risk; Role; Severity of illness; Signal Pathway; Signal Transduction; Specificity; Stress; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; United States; Up-Regulation; Venous Thrombosis; White Blood Cell Count procedure; Work; burden of illness; chemokine; cytokine; experimental study; hematopoietic stem cell differentiation; hematopoietic stem cell expansion; in vivo; in vivo Model; mortality; novel; novel therapeutics; precursor cell; progenitor; release of sequestered calcium ion into cytoplasm; response; stem cell population; stem cells; therapeutic target; thrombocytosis

Abstract In many inflammatory conditions such as inflammatory bowel disease (IBD) platelet counts rise, resulting in thrombocytosis, but what initiates this platelet up-regulation is not well understood. Thrombocytosis in IBD is a significant health concern, as it plays an active role in exacerbating disease morbidity. Increased platelet count and reactivity in patients with IBD correlate with disease severity, and platelets actively contribute to the mucosal inflammation and tissue-destructive inflammatory processes that are a hallmark of the disease. In addition, due to their elevated platelet counts, patients with IBD have an increased risk of venous thrombosis. As such, understanding the mechanisms driving this thrombocytosis and figuring out strategies to reverse it are important knowledge gaps to address. We have recently discovered a novel regulator of megakaryocyte (MK) differentiation and maturation known to be upregulated during inflammation, the inflammatory chemokine ligand 5 (CCL5, RANTES). Our preliminary data revealed that CCL5 administration to healthy mice leads to proliferation of hematopoietic stem cells (HSCs) and significantly increased platelet counts in the absence of increasing MK progenitors. These data suggest that CCL5 may act to increase platelet counts by mobilizing MK-biased HSCs. Consistent with this hypothesis, treatment of HSCs and MKs with CCL5 in vitro resulted in ehanced mitochondrial and cell cycle activity, respectively. Therefore, we hypothesize that CCL5 may induce thrombocytosis through activation of MK-biased HSCs, ultimately resulting in enhanced MK and platelet production. Furthermore, our previously published work established a role for CCL5 in driving platelet count in a murine IBD model. As such, our overall hypothesis is that CCL5 plays a role in inflammatory-mediated thrombocytosis in IBD. This proposal will elucidate the mechanism by which CCL5 affects HSC activation and differentiation in vitro (Aim 1) and in vivo (Aim 2). In addition, Aim 2 will examine the role of CCL5 on HSC activation in a murine IBD model.

抽象的 在许多炎症状态下，例如炎症性肠病（IBD）血小板计数增加，导致 血小板病，但引发该血小板上调的原因尚不清楚。 IBD中的血小板病是 严重的健康问题，因为它在加剧疾病发病率中发挥了积极作用。血小板计数增加 IBD患者的反应性与疾病严重程度相关，血小板积极促进 粘膜炎症和组织破坏性炎症过程是该疾病的标志。在 此外，由于血小板计数的升高，IBD患者患静脉血栓形成的风险增加。 因此，了解驱动这种血小板病的机制并弄清楚扭转策略的机制是 重要的知识差距要解决。我们最近发现了一个新颖的巨核细胞（MK）调节剂 炎症趋化因子在炎症期间已知已知上调的分化和成熟 配体5（CCL5，rantes）。我们的初步数据表明，CCL5对健康小鼠的给药导致 造血干细胞（HSC）的增殖，并在没有的情况下显着增加了血小板计数 增加MK祖细胞。这些数据表明，CCL5可以通过动员来增加血小板计数 MK偏向HSC。与该假设一致，在体外对HSC和MKs的处理导致 线粒体和细胞周期活性分别呈现。因此，我们假设CCL5可能诱发 通过激活MK偏置HSC的血小板病，最终导致MK和血小板增强 生产。此外，我们先前发表的工作确立了CCL5在驱动血小板计数中的作用 鼠IBD模型。因此，我们的总体假设是CCL5在炎症介导的 IBD中的血小板病。该提案将阐明CCL5影响HSC激活和 体外分化（AIM 1）和体内（AIM 2）。此外，AIM 2将检查CCL5在HSC中的作用 在鼠IBD模型中激活。