Exosome中miR-1281通过组蛋白去乙酰化介导血管新生的机制研究

Exosome secreted by stem cells can perform similar functions with those of transplanted stem cells in tissue repair. By transferring miRNAs and other bioactivators to target cells efficiently, exosomes play important roles in angiogenesis and tissue healing. Recent studies indicate that some miRNAs which are highly related to angiogenesis are highly-expressed specifically in exosome secreted by cells under hypoxia conditions. Our previous results also found the expression levels of certain miRNAs in exosome from stem cells affected by hypoxia were significantly changed, eg. miR-1281. Further in vitro experiments demonstrated that miR-1281 did apparently promote angiogenesis. In addition, bioinformatics analysis suggests histone deacetylases (HDACs) could be the targets of miR-1281. As all mentioned above, we plan to change the expressing level of miR-1281 in stem cells and analyze the alterations of HDACs and their down-stream genes related to angiogenesis in vascular endothelial cells affected by the exosomes from miR-1281 manipulated stem cells. Our study will illuminate the underlying mechanism of exosomal miR-1281 from stem cells promoting angiogenesis by regulating HDACs in target vascular endothelial. And we believe that this will set up the theoretical base of exosome applying for the treatment of ischemic diseases.

干细胞分泌的外泌体（Exosome）可以发挥与移植干细胞相类似的修复组织损伤功能，因其可高效传递miRNAs等活性物质到效应细胞，在促进血管新生和组织修复中发挥了重要作用。已有研究发现，缺氧环境下细胞分泌的Exosome中与血管新生密切相关的miRNAs特异性表达升高。我们的前期研究发现缺氧环境下培养干细胞分泌的Exosome中miRNAs出现了显著变化，尤其是miR-1281，进一步实验发现miR-1281可显著促进血管新生，生物信息学分析其靶向组蛋白去乙酰化酶。因此，本研究拟通过干扰或过表达干细胞中的miR-1281，明确Exosome传递miR-1281促进血管新生的功能，并研究miR-1281对HDACs及其下游效应基因的调控作用，明确miR-1281促进血管新生的分子机制。该研究将为优化Exosome辅助缺血性疾病的治疗提供理论依据。

干细胞分泌的外泌体可高效传递miRNAs等活性物质到效应细胞，在促进血管新生和组织修复中发挥了重要作用。本项目系统探讨了iPS-MSCs来源Exosome中miR-1281对血管新生的影响和作用途径。结果表明①缺氧环境下干细胞分泌的Exosome中miR-1281表达显著增加。②miR-1281可显著促进血管新生。③过表达/抑制miR-1281，其靶基因RND3表达明显下调/上调。④过表达miR-1281能显著激活Notch1蛋白，并引起STAT家族的磷酸化水平的变化。研究结果提示，miR-1281可靶向调控Rnd3基因的表达，进而诱导下游Notch信号通路的活化，STAT家族的磷酸化，进而共同调控血管生成；miR-1281-Rnd3-Notch通路可能是iPS-MSCs来源Exosome调控血管新生的主要信号通路之一。研究成果为优化Exosome辅助缺血性疾病的治疗提供了理论依据。