Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.
Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.
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DOI：
10.1161/circresaha.109.197723
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发表时间：
2009-05-22
影响因子：
20.1
通讯作者：
Qin G
中科院分区：
文献类型：
--
作者：
Tang YL;Zhu W;Cheng M;Chen L;Zhang J;Sun T;Kishore R;Phillips MI;Losordo DW;Qin G
心肌梗死(MI)会迅速耗尽内源性的心脏祖细胞库，而外源性应用的祖细胞的低效募集限制了心脏细胞治疗的有效性。最近的研究表明，CXC趋化因子基质细胞衍生因子1(SDF-1)与其受体CXC趋化因子受体4(CXCR4)之间的相互作用在缺血诱导的骨髓来源的循环干/祖细胞募集中起重要作用，但CXCR4在心脏前体细胞中的表达很低。在这里，我们研究了低氧对心肌前体细胞CXCR4表达的影响，对静脉给药细胞向缺血心脏组织的募集，以及对小鼠心肌梗死模型心功能的保护。我们发现低氧预适应增加了心肌来源的−/c-Kit+祖细胞CXCR4的表达，并显著增加了CLK细胞的迁移(体外)和募集(体内)到缺血心肌。在手术诱导心肌梗死四周后，接受低氧预适应CLK细胞治疗的小鼠的心肌梗死面积和心功能明显好于在常氧条件下培养的细胞治疗的小鼠。此外，CXCR4抑制剂的加入在很大程度上消除了这些影响，这表明低氧预适应的益处是通过SDF-1/CXCR4轴介导的，针对这一轴的治疗可能会加强基于心脏祖细胞的再生治疗。
Myocardial infarction (MI) rapidly depletes the endogenous cardiac progenitor-cell pool, and the inefficient recruitment of exogenously administered progenitor cells limits the effectiveness of cardiac-cell therapy. Recent reports indicate that interactions between the CXC chemokine stromal-cell–derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) critically mediate the ischemia-induced recruitment of bone-marrow—derived circulating stem/progenitor cells, but the expression of CXCR4 in cardiac progenitor cells is very low. Here, we studied the influence of hypoxia on CXCR4 expression in cardiac progenitor cells, on the recruitment of intravenously administered cells to ischemic heart tissue, and on the preservation of heart function in a murine MI model. We found that hypoxic preconditioning increased CXCR4 expression in cardiosphere-derived, Lin−/c-kit+ progenitor (CLK) cells and markedly augmented CLK-cell migration (in vitro) and recruitment (in vivo) to the ischemic myocardium. Four weeks after surgically induced MI, infarct size and heart function were significantly better in mice administered hypoxia-preconditioned CLK cells than in mice treated with cells cultured under normoxic conditions. Furthermore, these effects were largely abolished by the addition of a CXCR4 inhibitor, indicating that the benefits of hypoxic preconditioning are mediated by the SDF-1/CXCR4 axis, and that therapies targeting this axis may enhance cardiac-progenitor-cell—based regenerative therapy.