Mechanisms of myelopoiesis after myocardial infarction

心肌梗死后骨髓生成机制

• 批准号: 10625852
• 负责人: Partha Dutta
• 金额: $ 47.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625852
• 关键词: Acceleration; Acute; Adoptive Transfer; Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Binding Sites; Biological Assay; Blood; Blood Platelets; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; C57BL/6 Mouse; Cardiac Myocytes; Cell Count; Cells; Color; Data; Disease; Distant; Event; Exposure to; Flow Cytometry; Generations; HMGB1 gene; Heart; Hematopoietic stem cells; In Vitro; Infarction; Inflammation; Inflammatory; Injury; Interleukin-3 Receptor; Ischemia; Knockout Mice; Knowledge; Location; Low Density Lipoprotein Receptor; Luciferases; Magnetic Resonance Imaging; Measures; Mediating; Messenger RNA; Methylcellulose; MicroRNAs; Molecular; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Myocardial Infarction; Oils; Organ; Pathogenesis; Patients; Process; Production; Proliferating; Role; Signal Transduction; Sorting; Stains; Technology; Testing; Trichrome stain method; cytokine; drug development; extracellular vesicles; fluorescence molecular tomography; hematopoietic differentiation; improved; in silico; in vivo; intravital microscopy; ischemic injury; migration; mouse model; necdin; novel therapeutics; overexpression; progenitor; reconstitution; sham surgery; stem cell proliferation; stem cells; transcription factor; ultrasound

Project Summary/ Abstract: An acute injury, such as myocardial infarction (MI), induces exaggerated production of myeloid cells in the bone marrow. These newly generated myeloid cells are inflammatory and are crucial in disease pathogenesis, exacerbating underlying processes such as atherosclerosis. However, the systemic long distance signals and molecular mechanisms that trigger myelopoiesis in the bone marrow after an ischemic event at a distant organ, such as the heart, are poorly understood. Our preliminary data revealed that, following an MI, bone marrow hematopoietic stem and progenitor cells (HSPC) relocated into the vascular niches. Vascular niches confer distinct microenvironments promoting HSPC proliferation and differentiation. In investigating the long-distance signals produced after MI, we found increased levels of platelet-derived extracellular vesicles (pEV) in the blood of patients and mice after MI. These pEV increased the expression of PU.1, which is a myeloid transcription factor, and the receptor for interleukin-3 (IL-3R), which increases myeloid cell generation, in bone marrow HSPC. Additionally, pEV isolated from mice with MI contained high levels of miR-499, which increased bone marrow HSPC proliferation and differentiation in vitro. From these observations, we hypothesize that increased miR-499 in pEV following MI relocates HSPC to active vascular niches in the bone marrow, where they proliferate and differentiate into myeloid cells. We will test this hypothesis in two specific aims: (1) We will determine the role of pEV in relocation of HSPC to the vascular niches in the bone marrow. (2) We will investigate if increased miR-499 expression in pEV augments myelopoiesis and atherosclerosis after MI. To test the hypothesis, we will photoconvert KikGR+ HSPC, use mice deficient of miR-499 and two different mouse models of atherosclerosis. We will characterize pEV in patients and mice with MI using flow cytometry, ImageStream and NanoSight technologies. Additionally, we will determine the proliferation of HSPC exposed to pEV isolated from miR- 499+/+ and miR-499-/- mice after MI in vitro and in vivo. The proposed grant application will further our understanding of the mechanisms of MI-induced myelopoiesis, and explore new therapeutic avenues to diminish inflammation and atherosclerosis after MI.

项目摘要/摘要： 急性损伤，例如心肌梗塞（MI），诱导骨髓细胞在 骨髓。这些新产生的髓样细胞是炎症性的，对疾病至关重要 发病机理，加剧基本过程，例如动脉粥样硬化。但是，系统性长 距离信号和分子机制在缺血后触发骨髓中的髓鞘 远处的器官（例如心脏）的事件对此知之甚少。我们的初步数据表明， 在MI之后，骨髓造血茎和祖细胞（HSPC）重新安置到血管 利基。血管壁ches赋予促进HSPC增殖和分化的不同微环境。 在研究MI后产生的长距离信号时，我们发现血小板衍生的水平升高 MI后，患者和小鼠血液中的细胞外囊泡（PEV）。这些PEV增加了表达 Pu.1是髓样转录因子，以及介入介素3（IL-3R）的受体 骨髓HSPC中的髓样细胞产生。此外，从MI中分离出的PEV很高 miR-499的水平，在体外增加了骨髓HSPC增殖和分化。从这些 观察结果，我们假设MI之后PEV中的miR-499增加了HSPC为活性 骨髓中的血管壁细分市场，在那里它们扩散并分化为髓样细胞。我们将测试 这两个特定目的的假设是：（1）我们将确定PEV在搬迁HSPC中的作用 骨髓中的血管生态位。 （2）我们将研究PEV中的miR-499表达增加 MI后增强骨髓骨髓和动脉粥样硬化。为了检验假设，我们将摄取Kikgr+ HSPC，使用缺乏miR-499的小鼠和两种不同小鼠动脉粥样硬化模型。我们将 使用流式细胞术，成像级和纳米视线来表征患者和小鼠的PEV 技术。此外，我们将确定暴露于从miR-分离的PEV的HSPC的增殖 499+/+和miR-499 - / - 小鼠体外和体内。拟议的赠款申请将进一步 了解MI诱导的脊髓脉的机制，并探索新的治疗途径 MI后减少炎症和动脉粥样硬化。