联合EPC-EXs和NPC-EXs靶向于miR-126和miR-210治疗缺血性脑卒中

Ischemic stroke is the leading cause of death and long-term disability, which lacks effective treatments. Exosomes (EXs) can deliver microRNAs of their parent cells to affect the functions of receptor cells, and might be the responsible mechanism for stem cell-based therapy. We have found that co-culture of endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) can synergistically protect ECs and neurons against hypoxic injury by respectively activating the VEGF/VEGFR2/PI3k/Akt and BDNF/TrkB/PI3k/Akt pathways. It is well known that miR-126 and miR-210 can respectively target VEGF and BDNF to exhibit anti-oxidative and anti-apoptotic effects on cells. Our preliminary data demonstrate that co-culture of EPC-EXs and NPC-EXs can protect ECs and neurons against hypoxic injury and that miR-126 enriched EPC-EXs (EPC-EXsmiR-126) can more effectively improve cerebral blood perfusion in ischemic stroke mice. In this proposal, we aim to investigate whether EPC-EXsmiR-126 and NPC-EXsmiR-210 can synergistically ameliorate ischemia-induced acute cerebral injury and promote cerebral tissue repair, and explore the underlining mechanisms. The findings of this study will provide a novel therapeutic approach for ischemic stroke. Therefore, our study holds strong scientific significance and great practical prospect.

缺血性脑卒中发病率和致死率高，缺少有效的治疗。细胞外泌体（EXs）能通过传递其携带母细胞的miRNAs等分子影响受体细胞功能，可能是干细胞治疗作用的重要途径。我们发现内皮祖细胞（EPCs）及神经祖细胞（NPCs）共培养协同性降低血管内皮细胞（ECs）及神经细胞缺氧损伤，与分别激活VEGF/VEGFR2和 BDNF/TrkB通路靶向PI3k/Akt有关。已知miR-126和miR-210能分别靶向VEGF和BDNF发挥抗氧化/抗凋亡作用。前期工作表明EPC-EXs联合NPC-EXs 能协同性保护ECs和神经细胞，富含miR-126的EPC-EXs （EPC-EXsmiR-126）更有效改善脑卒中小鼠脑血流灌注。本项目拟探索EPC-EXsmiR-126和NPC-EXs miR-210是否协同性地减轻脑缺血性损伤和促进修复，及相关机制。为治疗缺血性脑卒中提供新途径，有很强的科学意义和应用前景。

缺血性脑卒中( IS)的发病率和致死率高，缺少有效的治疗。细胞外泌体（EXs）能通过传递其携带的母细胞的miRNAs (miRs)等分子影响受体细胞功能，并可能是干细胞治疗作用的重要途径。本项目在已有报道和前期研究基础上，旨在探索联合内皮祖细胞外泌体（EPC-EXs）和神经祖细胞外泌体（NPC-EXs）靶向于miR-126和miR-210治疗缺血性脑卒中的作用。体外细胞实验中，本项目检测了富含miR-126 的EPC-EXs（EPC-EXsmiR-126）和富含miR-210的NPC-EXs（NPC-EXs miR-210）对受体细胞ECs和神经元功能的协同性调控作用，并深入探讨相关机制；体内研究中，探索输注EPC-EXsmiR-126和NPC-EXsmiR-210对IS小鼠脑缺血损伤的协同性保护及治疗作用。我们研究发现，与EPC-EXs和NPC-EXs相比，EPC-EXsmiR-126和NPC-EXsmiR-210能通过传递携带的miR-126和miR-210，调控VEGF/VEGFR、 NOX2/ ROS和BDNF/TrkB通路对缺氧损伤ECs和神经元细胞功能的发挥更好的保护作用，更有效地改善 IS小鼠神经血管损伤，促进血管生成和神经再生，两者联合使用保护作用更强。本研究阐明了富含miR-126的EPC-EXs和富含miR-210的NPC-EXs能协同性的保护脑缺血性损伤，对IS发挥更好的治疗效果。本项目共发表相关论文6篇。项目的研究成果对基础及临床研究均具有较高的指导意义，为血管和神经功能调控及IS治疗研究提供新的靶标及策略，具有很强的科学意义及临床应用前景。