Polymer-DNA Nanoparticle-Induced CXCR4 Overexpression Improves Stem Cell Engraftment and Tissue Regeneration in a Mouse Hindlimb Ischemia Model.
Polymer-DNA Nanoparticle-Induced CXCR4 Overexpression Improves Stem Cell Engraftment and Tissue Regeneration in a Mouse Hindlimb Ischemia Model.
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作者：
Deveza L;Choi J;Lee J;Huang N;Cooke J;Yang F
周围动脉疾病影响着全世界近 2.02 亿人，严重时有时会导致无法愈合的溃疡或截肢。转基因干细胞通过增强旁分泌释放机制并调整疾病部位对环境刺激的动态反应，为治疗诱导血管生成提供了潜在的优势。在这里，我们报告了纳米颗粒诱导的 CXCR4 过表达干细胞在小鼠后肢缺血模型中的应用。我们发现 CXCR4 过度表达可改善干细胞存活、调节原位炎症并加速血液再灌注。出乎意料的是，这些效应导致了完整的肢体挽救和骨骼肌修复，明显优于传统的血管生成因子控制 VEGF 的功效。重要的是，对 CXCR4 过度表达干细胞的体外评估表明，CXCR4 过度表达诱导干细胞旁分泌信号的变化，促进治疗上所需的促血管生成和抗炎表型。这些结果表明，纳米颗粒诱导的 CXCR4 过度表达可能促进干细胞响应缺血环境的有利表型变化和治疗功效。
Peripheral arterial disease affects nearly 202 million individuals worldwide, sometimes leading to non-healing ulcers or limb amputations in severe cases. Genetically modified stem cells offer potential advantages for therapeutically inducing angiogenesis via augmented paracrine release mechanisms and tuned dynamic responses to environmental stimuli at disease sites. Here, we report the application of nanoparticle-induced CXCR4-overexpressing stem cells in a mouse hindlimb ischemia model. We found that CXCR4 overexpression improved stem cell survival, modulated inflammation in situ, and accelerated blood reperfusion. These effects, unexpectedly, led to complete limb salvage and skeletal muscle repair, markedly outperforming the efficacy of the conventional angiogenic factor control, VEGF. Importantly, assessment of CXCR4-overexpressing stem cells in vitro revealed that CXCR4 overexpression induced changes in paracrine signaling of stem cells, promoting a therapeutically desirable pro-angiogenic and anti-inflammatory phenotype. These results suggest that nanoparticle-induced CXCR4 overexpression may promote favorable phenotypic changes and therapeutic efficacy of stem cells in response to the ischemic environment.