Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration
Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration
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DOI：
10.3390/ijms20030468
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Barile, Lucio
中科院分区：
文献类型：
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作者：
Ciullo, Alessandra;Biemmi, Vanessa;Barile, Lucio
细胞疗法已被评估为增强损伤后的心脏功能。递送的细胞主要通过旁分泌机制起作用，包括分泌的生长因子、细胞因子和囊泡，如外泌体（Exo）。心肌内注射心脏驻留祖细胞（CPC）衍生的Exo可减少大鼠心肌梗死后的瘢痕形成并改善心功能。在这里，我们探索了一种临床相关的方法，以增强归巢过程中的心肌细胞（CM），这是至关重要的治疗效果后，全身交付的Exo。通过过量表达外泌体CXCR 4，我们通过增加其对缺血心脏的生物利用度来增加血浆注射心脏保护性Exo-CPC的功效。与Exo（CTRL）相比，静脉内注射Exo（CXCR 4）在4周时显著减小梗死面积并改善左心室射血分数（p < 0.01）。血流动力学测量显示，与Exo（CTRL）和PBS组相比，Exo（CXCR 4）改善dp/dt min。在体外，Exo（CXCR 4）在预防CM死亡方面比Exo（CTRL）更具生物活性。如使用AMD 3100作为特异性CXCR 4拮抗剂所示，这种体外作用不依赖于SDF-1。我们首次表明，全身给予源自CXCR 4过表达CPC的Exo可改善缺血再灌注损伤大鼠模型的心脏功能。这些数据代表了基于Exo的治疗方法在心血管疾病临床应用方面迈出的实质性一步。
Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of Exo(CXCR4) significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo(CTRL) (p < 0.01). Hemodynamic measurements showed that Exo(CXCR4) improved dp/dt min, as compared to Exo(CTRL) and PBS group. In vitro, Exo(CXCR4) was more bioactive than Exo(CTRL) in preventing CM death. This in vitro effect was independent from SDF-1, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.