The Role of CCL5 in Hematopoietic Stem Cell Activation and Skewing

摘要 在许多炎性病症如炎性肠病（IBD）中，血小板计数升高，导致血小板减少。 血小板增多症，但什么启动这种血小板上调还没有很好地理解。IBD中的血小板增多症是一种 这是一个严重的健康问题，因为它在加剧疾病发病率方面起着积极作用。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，血小板积极促进炎症性肠病的发生。 粘膜炎症和组织破坏性炎性过程，这是该疾病的标志。在 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症的驱动机制并找出逆转它的策略是非常重要的。 重要的知识缺口。我们最近发现了一种新的巨核细胞（MK）调节因子 已知在炎症过程中分化和成熟上调，炎性趋化因子 配体5（CCL5，RANTES）。我们的初步数据显示，对健康小鼠施用CCL5会导致 造血干细胞（HSC）增殖和血小板计数显著增加， 增加MK祖细胞。这些数据表明，CCL5可能通过动员血小板来增加血小板计数。 MK偏向的HSC。与这一假设相一致，在体外用CCL5处理HSC和MK导致 分别增强线粒体和细胞周期活性。因此，我们假设CCL5可能诱导 通过激活MK偏向的HSC，最终导致MK和血小板增多， 生产此外，我们先前发表的工作确定了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在炎症介导的炎症反应中起作用。 IBD中的血小板增多。该提案将阐明CCL5影响HSC活化的机制， 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模型中的活化。

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.