CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells
CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells
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CXCR4基因转移有助于内皮祖细胞的体内再内皮化能力
DOI：
10.1093/cvr/cvq207
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发表时间：
2010-12-01
影响因子：
10.8
通讯作者：
Tao, Jun
中科院分区：
文献类型：
--
作者：
Chen, Long;Wu, Fang;Tao, Jun
内皮祖细胞（EPCs）在动脉损伤后的内皮修复中发挥关键作用。趋化因子受体CXCR 4是EPCs归巢受损动脉和再内皮化的关键调节因子。本研究以CXCR 4基因转染的EPCs为研究对象，体外扩增EPCs，并将CXCR 4基因转染人EPCs。在体外，CXCR 4基因转移增强EPC迁移和增强EPC粘附内皮细胞单层。流动条件下的粘附试验表明，CXCR 4基因转移增加了EPCs对纤连蛋白的阻滞能力。为了确定CXCR 4基因转移是否促进治疗性再内皮化，在颈动脉损伤的裸鼠中检查了EPCs对体内再内皮化的作用。与载体相比，移植有或没有基因转移的EPCs显着加速在体内再内皮化;然而，移植与Ad 5/CXCR 4转导的EPCs有进一步增强的效果与对照EPCs相比，含有EPCs与编码增强型绿色荧光蛋白基因的腺病毒转导或未转导的EPCs。我们还发现，磷酸化的Janus激酶-2（JAK-2），CXCR 4下游信号转导靶点，在用Ad 5/CXCR 4转导的EPCs中增加。CXCR 4基因转染增强的EPCs体外功能和体内再内皮化能力可被CXCR 4中和抗体或/和JAK-2抑制剂AG 490阻断。CXCR 4在人EPCs中的上调可能成为内皮修复的新的治疗靶点。
Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair after artery injury. The chemokine receptor CXCR4 is a key modulator of the homing of EPCs to impaired artery and reendothelialization. In this study, we addressed the hypothesis that CXCR4 gene transfer could enhance the reendothelialization capacity of EPCs.In vitro, human EPCs were expanded and transduced with adenovirus serotype 5 encoding the human CXCR4 gene (Ad5/CXCR4). In vitro, CXCR4 gene transfer augmented EPC migration and enhanced EPC adhesion to endothelial cell monolayers. Adhesion assays under flow conditions showed that CXCR4 gene transfer increased the ability of EPCs to arrest on fibronectin. To determine whether CXCR4 gene transfer facilitated therapeutic reendothelialization, the effect of EPCs on in vivo reendothelialization was examined in nude mice subjected to carotid artery injury. Compared with the vehicle, transplantation of EPCs with or without gene transfer significantly accelerated in vivo reendothelialization; however, transplantation of EPCs transduced with Ad5/CXCR4 had a further enhanced effect compared with control EPCs containing EPCs transduced with an adenovirus encoding enhanced green fluorescent protein gene or non-transduced EPCs. We also found that phosphorylation of Janus kinase-2 (JAK-2), a CXCR4 downstream signalling target, was increased in EPCs transduced with Ad5/CXCR4. The enhanced in vitro function and in vivo reendothelialization capacity of EPCs by CXCR4 gene transfer were abolished by neutralizing antibodies against CXCR4 or/and JAK-2 inhibitor AG490.The present study demonstrates that CXCR4 gene transfer contributes to the enhanced in vivo reendothelialization capacity of EPCs. Up-regulation of CXCR4 in human EPCs may become a novel therapeutic target for endothelial repair.