Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI.
Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI.
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DOI：
10.1038/ncpcardio0430
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发表时间：
2006-03-01
影响因子：
--
通讯作者：
Losordo, Douglas W
中科院分区：
文献类型：
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作者：
Shintani, Satoshi;Kusano, Kengo;Losordo, Douglas W
先前的研究表明，局部血管生成基因治疗的作用，部分是通过招募内皮祖细胞（EPCs）缺血组织。最近的数据表明，患有最严重血管疾病的患者可能具有不足或缺陷的EPCs，并且对血管生成治疗的反应最差。因此，我们假设联合人CD 34（+）细胞移植和局部血管内皮生长因子2（phVEGF 2）基因治疗可能克服这些缺陷。向EPC培养物中加入VEGF 2导致EPC凋亡显著且呈剂量依赖性减少。磷酸化Akt（p-Akt）在VEGF 2处理的EPCs中增加。在体内，通过结扎34只免疫缺陷大鼠的冠状动脉左前降支诱导心肌梗死（MI）。然后将动物随机分配到四个治疗组中的一个：单独使用人CD 34（+）细胞的细胞治疗;单独使用VEGF 2基因治疗; CD 34（+）细胞加phVEGF 2的联合治疗;或CD 34（-）细胞和50 μ g空质粒。MI后4周，与其他三组相比，联合治疗组的动物显示缩短分数改善，毛细血管密度增加，梗死面积减少。联合治疗也与MI后1周循环EPCs数量增加相关。与单一疗法相比，细胞和基因疗法的组合亚治疗剂量产生显著的治疗效果。这种方法可以克服治疗失败（例如，某些患者无法动员足够的EPC），并且还可以通过允许较低剂量策略提供安全性优势。
Previous studies have shown that local angiogenic gene therapy acts, in part, by recruiting endothelial progenitor cells (EPCs) to ischemic tissue. Recent data indicate that patients with the most severe vascular disease may have insufficient or deficient EPCs and the poorest response to angiogenic therapy. Accordingly, we hypothesized that combining human CD34(+) cell implantation with local vascular endothelial growth factor 2 (phVEGF2) gene therapy might overcome these deficiencies. The addition of VEGF2 to EPC cultures resulted in significant and dose-dependent decreases in EPC apoptosis. Phosphorylated Akt (p-Akt) was increased in VEGF2-treated EPCs. In vivo, myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in 34 immunodeficient rats. The animals were then randomized to one of four treatment groups: cell therapy alone with human CD34(+) cells; VEGF2 gene therapy alone; combination therapy with CD34(+) cells plus phVEGF2; or CD34(-) cells and 50 microg empty plasmid. Four weeks after MI, animals treated with combination therapy showed improved fractional shortening, increased capillary density, and reduced infarct size compared with the other three groups. Combination therapy was also associated with an increased number of circulating EPCs 1 week after MI. Combined subtherapeutic doses of cell and gene therapy result in a significant therapeutic effect compared to monotherapy. This approach may overcome therapeutic failures (e.g. inability of certain patients to mobilize sufficient EPCs) and may also offer safety advantages by allowing lower dosing strategies.