间充质干细胞源性外泌体通过miR-22促进静脉畸形内皮细胞凋亡的分子机制

Venous malformations(VM) are congenital vascular dysplasia disease, which are the most common type of vascular malformations. There is still a lack of safe and effective treatment for large-scale, multiple, and deep-lying lesions. Previous studies have shown that venous malformation endothelial cells were resistant to apoptosis and resulted from over-activation of PI3K/AKT signaling pathway. Our preliminary works found that the anti-apoptotic ability of endothelial cells was decreased and the level of PI3K/AKT activation was down regulated after co-culturing with mesenchymal stem cells which may be related to the regulation of stem cell derived exosomes. And this change may be further enhanced by miR-22-enriched exosomes. The purpose of this project is to investigate the role of mesenchymal stem cells in regulating the apoptosis of venous malformation endothelial cells through the paracrine effect of exosomes, and to further investigate the specific mechanism of miR-22-mediated PI3K/AKT signaling pathway in this process. Experiments are to be conducted in vitro and in animal models to explore the possibility of using mesenchymal stem cells and miR-22-enriched exosomes to treat large-scale, multiple, and deep-lying VM.

静脉畸形是一种先天性血管发育异常性疾病，属于脉管畸形中的最常见类型，对于大范围、多发性、深在病变临床上仍缺乏安全有效的治疗手段。现有文献及本课题组前期研究表明静脉畸形内皮细胞抗凋亡能力增强，并与PI3K/AKT异常活化相关。课题组前期实验发现间充质干细胞与静脉畸形内皮细胞共培养后PI3K/AKT活化水平下调，内皮细胞抗凋亡能力下降，这一改变可能通过富含miR-22的干细胞源性外泌体进一步加强。本项目旨在研究间充质干细胞通过外泌体的旁分泌效应对静脉畸形内皮细胞凋亡的调控作用，并深入探讨miR-22介导的PI3K/AKT信号通路在这一过程的具体机制。实验拟在体外细胞水平和动物模型中进行，探讨间充质干细胞及其富含miR-22的外泌体治疗大型、多发性静脉畸形的可能性。

静脉畸形是临床中最常见的脉管畸形，可随机体年龄增长而缓慢增大。目前对于大范围的、位于关键解剖部位的，多发性的病变临床上仍缺乏安全、有效的治疗手段。本研究首次分析了miR-22在静脉畸形中的表达水平，并尝试分析其对静脉畸形内皮细胞的调控作用。首次应用骨髓间充质干细胞与静脉畸形内皮细胞模型进行共培养，发现其通过干细胞源性外泌体下调异常活化的PI3K/AKT信号通路，进而降低静脉畸形内皮细胞的抗凋亡能力，促进内皮细胞凋亡。本研究为静脉畸形的临床治疗提供了新思路。