EPCs源性外泌体介导miR-126促血管生成对脓毒症血管内皮损伤的保护作用及其机制

内皮细胞的损伤和激活在脓毒症的发生中具有重要的作用。作为内皮细胞的前体，血管内皮祖细胞（EPCs）分化增殖为内皮细胞或以旁分泌效应修复损伤的血管内皮。本课题组前期研究已证实EPCs移植增加鼠缺血后肢新生血管形成、促进缺血心肌血管形成，增加心肌局部收缩力，改善心功能。外泌体作为一种细胞分泌到胞外的囊泡状小体，广泛参与各种疾病生理及病理过程。EPCs分泌的外泌体，特别是其内容物miRNAs，激活内皮细胞分泌各种生物活性物质，参与缺血组织的血管发生和血管损伤后的修复。本研究通过以EPCs来源的外泌体中的微小RNA-126作为研究对象，深入探讨EPCs刺激血管内皮细胞内源性修复效应的分子机制，并应用EPCs来源的外泌体治疗脓毒症血管内皮损伤，试图以外泌体这一新的医学发现来攻克危重病医学领域的研究热点和难点，为脓毒症的治疗开辟新的途径，也为更好地应用成体干/祖细胞治疗人类疾病提供新的思路。

Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure.Endothelial progenitor cells(EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA(miRNA),however,the underlying mechanisms remain obscure.Our previous studies have indicated that bone marrow-derived endothelial progenitor cells,as vascular endothelium precursor cells,augmented neovascularization in ischemia hindlimb and myocardium,increased myocardial local contractility and improved cardiac function.Numerous studies have indicated that exosomes play critical roles in mediating cell-to-cell communication.Exosomes are believed to possess a powerful capacity in regulating cell survival/death,inflammation and angiogenesis,depending on the particular array of molecules contained within a particular population of exosomes.Recent evidence indicates that EPCs-derived exosome can promote angiogenesis of endothelial cells. MicroRNAs regulate gene expression posttranscriptionally and function within the cells in which they are.transcribed.Here, we investigated the angiogenesis effects of EPCs-derived exosome on endotoxin(LPS) in human brain endothelial cell(hb-ECs) in vitro.We examined in this study whether blocking the generation of exosomes would be protetive against LPS-induced inflammatory response and endothelial dysfunction. Finally,an in vivo sepsis model confirmed the protect effects of exosomal miR-126 derived fromEPCs.We aimed to investigate exosomal miR-126 derived from EPCs for therapeutic angiogenesis in sepsis.The aim of this study is to observe the endothelium repair and angiogenesis and to investigate the protective effects and its molecular mechanisms of EPCs exosomes on sepsis .This study will provide a potential way for sepsis therapy and a novel therapeutic idea for the application of mature stem cells transplanation in human diseases.