血小板源胞外囊泡通过miR-499/Necdin通路促进心肌梗死后骨髓造血干/祖细胞增殖及髓系分化的机制研究

心肌梗死所致的局部损伤可远程作用于骨髓，诱导其过度增殖并分化为促炎表型的髓系细胞，加剧心梗后动脉粥样硬化进展，但具体机制尚未阐明。我们前期证实心梗后造血干/祖细胞(HSPC)在血管内皮细胞龛（niche）中的异常增殖可促进粥样斑块发展。在心梗患者及小鼠血液中，血小板源胞外囊泡（pEVs）的数量显著增加，其中miR-499明显升高，抑制靶基因Necdin的表达。据此我们提出假说：心梗后pEVs分泌增加，通过miR-499/Necdin通路促进HSPC增殖分化，最终加剧粥样斑块进展。本项目拟从动物、细胞及临床水平阐明pEVs对心梗后HSPC增生的作用；探讨pEVs-miR-499/Necdin通路对心梗后造血细胞增殖的调控机制；明确心梗患者血液pEVs中miR-499水平与心梗后粥样斑块进展的临床相关性。本研究将以pEVs-miRNA为新视点，寻找防治心梗后动脉粥样硬化进展的新型干预靶点。

Ischemic injury, such as myocardial infarction (MI), induces exaggerated production of myeloid cells (myelopoiesis), which are crucial to atherosclerosis exacerbation after MI. However, the systemic long-distance signals and molecular mechanisms that trigger myelopoiesis from hematopoietic stem and progenitor cells (HSPC) in the bone marrow after an ischemic event at a distant organ, such as the heart, are poorly understood. Our preliminary data revealed that MI increased HSPC numbers in bone marrow vascular niches, which are 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 (pEVs) in the blood of patients and mice after MI. Additionally, pEVs isolated from mice with MI contained high levels of miR-499, which might decrease the expression of Necdin to induce HSPC proliferation and myeloid cell generation. From these observations, we hypothesize that the pEVs-miR-499/Necdin pathway promotes the proliferation and differentiation of HSPC, which augments myelopoiesis and atherosclerosis after MI. 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.