细胞外泌体增强侧支血管新生促进卒中二级预防的策略与机制研究

缺血性卒中常导致终生残疾，预防残疾的关键在于卒中急性期即二级预防阶段就进行有效干预。研究发现卒中后侧支循环建立越早越充分，残疾率越小。如何早期改善侧支循环，目前尚无有效策略。缺血性血管病的侧支循环建立主要依赖于血管新生，既往血管新生研究多集中在中晚期康复阶段。细胞外泌体是重要的细胞间通讯媒介，可以促进血管新生和神经再生，且可以透过血脑屏障和低免疫原性，在卒中急性期作为干预手段极具有优势。另外提高外泌体的靶向性会高效促进血管新生，而外泌体的导向研究较少。基于我们的临床和预实验结果，我们假设：1、在大鼠卒中模型急性期静脉补充细胞外泌体，可以促进缺血区血管新生，改善侧支循环，减少神经功能损伤；2、通过CXCR4基因修饰的细胞外泌体可以增强其靶向性，更有效地到达缺血区，高效促进侧支循环建立。探索外泌体膜受体介导的细胞导向作用是本课题重要创新点。本课题将为卒中二级预防提供早期干预策略。

Ischemic stroke often leads to lifelong disability. Secondary prevention in the acute ischemic stage is the key to prevent disability. The sufficient early collateral circulation establishment is the key to prevent disability, more collateral circulation leads to lower disability.. There is no effective strategy to improve the collateral circulation in the early stage so far. The collateral circulation in the ischemia area mainly depends on angiogenesis. Previous studies on angiogenesis have been focused in the rehabilitation stage. Exosomes are important intercellular communication mediators which can promote angiogenesis and nerve regeneration. Exosomes can penetrate the blood-brain barrier and have low immunogenicity, so they have great advantages as interventions for angiogenesis in the acute stage of stroke. Diverting exosomes to the ischemic area may effectively promote collateral angiogenesis there. There are few studies on exosome targeting. Based on our promising preliminary data, we hypothesized that: 1) Intravenous administration of exosomes during the acute phase of stroke could promote collateral blood vessel regeneration in the ischemic area, improve collateral circulation and reduce nerve function damage in a rat stroke model; 2) Modification of exosomes by CXCR4 gene could induce exosomes moving into the ischemic area efficiently, enhance collateral vessel angiogenesis, and improve neurological function. Exploring exosome membrane receptor-mediated cell-directing is an important innovation. This study will offer novel scientific mechanisms and early intervention strategies for secondary prevention of stroke.