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.

摘要 在许多炎症性疾病中，如炎症性肠病(IBD)，血小板计数上升，导致 血小板增多，但启动这种血小板上调的原因还不是很清楚。IBD中的血小板增多症是一种 这是一个重大的健康问题，因为它在加剧疾病发病率方面发挥了积极作用。血小板计数增加 炎症性肠病患者的反应性与疾病的严重程度相关，而血小板对 粘膜炎症和组织破坏性炎症过程是该病的标志。在……里面 此外，由于血小板计数升高，IBD患者静脉血栓形成的风险增加。 因此，了解这种血小板增多的机制并找出逆转它的策略是 需要解决的重要知识差距。我们最近发现了一种新的巨核细胞(MK)调节因子 已知的分化和成熟在炎症过程中上调，炎性趋化因子 配体5(CCL5，RANTES)。我们的初步数据显示，给健康小鼠注射CCL5会导致 造血干细胞(HSCs)的增殖和血小板计数的显著增加 增加MK祖细胞。这些数据表明，CCL5可能通过动员增加血小板计数。 偏向于MK的造血干细胞。与这一假设一致，体外用CCL5处理HSCs和MKs导致 线粒体活性和细胞周期活性分别增强。因此，我们假设CCL5可能诱导 通过激活偏向于MK的HSCs而导致的血小板增多，最终导致MK和血小板增加 制作。此外，我们之前发表的工作确立了CCL5在推动血小板计数中的作用 一种小鼠IBD模型。因此，我们的总体假设是CCL5在炎症介质中发挥作用 炎症性肠病的血小板增多症。这一建议将阐明CCL5影响HSC激活和 体外分化(Aim 1)和体内分化(Aim 2)。此外，目标2将研究CCL5对HSC的作用 在小鼠IBD模型中的激活。