Bone marrow CXCR4 induction by cultivation enhances therapeutic angiogenesis
Bone marrow CXCR4 induction by cultivation enhances therapeutic angiogenesis
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DOI：
10.1093/cvr/cvn247
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发表时间：
2009-01-01
影响因子：
10.8
通讯作者：
Ikeda, Uichi
中科院分区：
文献类型：
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作者：
Shiba, Yuji;Takahashi, Masafumi;Ikeda, Uichi
趋化因子基质细胞衍生因子-1（SDF-1）及其受体（CXCR 4、CXC趋化因子受体4）在出生后新生血管形成过程中发挥关键作用。在此，我们研究了CXCR 4（+）骨髓细胞（BMCs）在小鼠后肢缺血模型中的新生血管形成中的作用，我们发现CXCR 4在BMCs中的表达通过培养而特异性上调，因此，我们使用新鲜分离的BMCs和培养的BMCs，分别命名为BMCFr和BMCCul。增加的CXCR 4表达对应于响应SDF-1 α的迁移能力。实时逆转录-聚合酶链反应和免疫组化分析显示，SDF-1 α表达在小鼠缺血肢体中显著增加。与植入BMCFr的小鼠相比，植入BMCCul的小鼠的血流灌注和毛细血管密度显著加快。当植入来源于CXCR 4（+/-）小鼠的BMCCul时，BMCCul对新血管形成的刺激作用显著受损。植入的BMCCul在缺血肢体中显示出高保留。此外，BMCCul的植入显著增加了缺血肢体中白细胞介素（IL）-1 β和血管内皮生长因子-AXCR 4表达的上调可以作为用于加速缺血性心血管疾病中的治疗性血管生成的有用的BMCs来源。
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor (CXCR4, CXC chemokine receptor 4) play a critical role in the process of post-natal neovascularization. Here, we investigated the role of CXCR4(+) bone marrow cells (BMCs) in neovascularization in a murine hindlimb ischaemia model.We found that the expression of CXCR4 in BMCs was specifically upregulated by cultivation; therefore, we used freshly isolated BMCs and cultivated BMCs, designated as BMCFr and BMCCul, respectively. The increased CXCR4 expression corresponded to the migratory capacity in response to SDF-1 alpha. Real-time reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that SDF-1 alpha expression was significantly increased in the ischaemic limbs of mice. Blood flow perfusion and capillary density were significantly accelerated in mice implanted with BMCCul as compared with those in mice implanted with BMCFr. The stimulatory effect of BMCCul on neovascularization was significantly impaired when BMCCul derived from CXCR4(+/-) mice were implanted. The implanted BMCCul showed high retention in the ischaemic limbs. Further, the implantation of BMCCul significantly increased the expression of interleukin (IL)-1 beta and vascular endothelial growth factor-A in the ischaemic limbs.The upregulation of CXCR4 expression by cultivation may serve as a useful source of BMCs for accelerating therapeutic angiogenesis in ischaemic cardiovascular diseases.