Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia
Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia
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细胞介导的 VEGF 修饰 mRNA 递送可增强血管再生并改善小鼠严重肢体缺血。
DOI：
10.1016/j.jconrel.2019.08.014
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发表时间：
2019-09-28
影响因子：
10.8
通讯作者：
Chien，Kenneth R.
中科院分区：
文献类型：
--
作者：
Yu，Ziyou;Witman，Nevin;Chien，Kenneth R.
编码血管内皮生长因子（VEGF）的合成化学修饰mrna （modRNA）是治疗缺血性心血管损伤的一种替代基因疗法。然而，需要新的modRNA递送方法来提高患病环境的治疗效果。我们假设细胞介导的modRNA递送可能会增强VEGF蛋白的体内表达动力学，从而促进更有效的血管生成作用。在这里，我们使用皮肤成纤维细胞作为“概念证明”来探索细胞介导的mRNA传递系统在小鼠重度肢体缺血（CLI）模型中的治疗潜力。我们发现，用VEGF modRNA预处理的成纤维细胞有可能完全挽救缺血肢体。通过详细的分子分析，我们发现，与对照组和载体组相比，成纤维细胞- vegf modRNA联合治疗显著减少了cli损伤肢体的组织坏死，并显著提高了血管密度。此外，成纤维细胞传递的VEGF modRNA处理增加了Pax7+卫星细胞的存在，表明VEGF与卫星细胞活性之间可能存在相关性。我们的研究首次证明了细胞介导的modRNA治疗可能是心血管疾病的另一种先进策略。
Synthetic chemically modified mRNAs (modRNA) encoding vascular endothelial growth factor (VEGF) represents an alternative to gene therapy for the treatment of ischemic cardiovascular injuries. However, novel delivery approaches of modRNA are needed to improve therapeutic efficacy in the diseased setting. We hypothesized that cell-mediated modRNA delivery may enhance thein vivoexpression kinetics of VEGF protein thus promoting more potent angiogenic effects. Here, we employed skin fibroblasts as a “proof of concept” to probe the therapeutic potential of a cell-mediated mRNA delivery system in a murine model of critical limb ischemia (CLI). We show that fibroblasts pre-treated with VEGF modRNA have the potential to fully salvage ischemic limbs. Using detailed molecular analysis we reveal that a fibroblast-VEGF modRNA combinatorial treatment significantly reduced tissue necrosis and dramatically improved vascular densities in CLI-injured limbs when compared to control and vehicle groups. Furthermore, fibroblast-delivered VEGF modRNA treatment increased the presence of Pax7+satellite cells, indicating a possible correlation between VEGF and satellite cell activity. Our study is the first to demonstrate that a cell-mediated modRNA therapy could be an alternative advanced strategy for cardiovascular diseases.