Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit.
Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit.
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DOI：
10.1016/b978-0-12-398459-3.00011-3
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发表时间：
2012
影响因子：
--
通讯作者：
Qin, Gangjian
中科院分区：
文献类型：
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作者：
Cheng, Min;Qin, Gangjian
祖细胞的保留和释放主要受基质细胞衍生因子1（SDF-1）与CXC趋化因子受体4（CXCR 4）的结合和α4-整联蛋白信号传导的控制。这两种途径都依赖于c-kit活性：响应CXCR 4拮抗或α4-整联蛋白阻断的祖细胞动员因c-kit激酶活性丧失而受损; c-kit激酶失活阻断了骨髓中CXCR 4阳性祖细胞的保留。SDF-1/CXCR 4和α4-整合素信号传导对于缺血区域中祖细胞的保留也是至关重要的，这可以至少部分解释为什么祖细胞治疗的临床试验未能显示在临床前研究中观察到的疗效。缺乏有效性通常归因于移植细胞的保留差，并且迄今为止，大多数试验方案都通过注射粒细胞集落刺激因子（G-CSF）动员细胞，G-CSF激活细胞外蛋白酶，其不可逆地切割细胞表面粘附分子，包括α4-整联蛋白和CXCR 4。因此，G-CSF动员的细胞在缺血区域的滞留可能受损，可逆性破坏SDF-1/CXCR 4结合的药物（如AMD 3100）的动员可能改善患者反应。在缺血区域补充SDF-1水平的努力也可能改善祖细胞募集和干细胞治疗的有效性。
Progenitor cell retention and release are largely governed by the binding of stromal-cell-derived factor 1 (SDF-1) to CXC chemokine receptor 4 (CXCR4) and by α4-integrin signaling. Both of these pathways are dependent on c-kit activity: the mobilization of progenitor cells in response to either CXCR4 antagonism or α4-integrin blockade is impaired by the loss of c-kit kinase activity; and c-kit–kinase inactivation blocks the retention of CXCR4-positive progenitor cells in the bone marrow. SDF-1/CXCR4 and α4-integrin signaling are also crucial for the retention of progenitor cells in the ischemic region, which may explain, at least in part, why clinical trials of progenitor cell therapy have failed to display the efficacy observed in preclinical investigations. The lack of effectiveness is often attributed to poor retention of the transplanted cells and, to date, most of the trial protocols have mobilized cells with injections of granulocyte colony-stimulating factor (G-CSF), which activates extracellular proteases that irreversibly cleave cell-surface adhesion molecules, including α4-integrin and CXCR4. Thus, the retention of G-CSF-mobilized cells in the ischemic region may be impaired, and the mobilization of agents that reversibly disrupt SDF-1/CXCR4 binding, such as AMD3100, may improve patient response. Efforts to supplement SDF-1 levels in the ischemic region may also improve progenitor cell recruitment and the effectiveness of stem cell therapy.