Concurrent Blockade of α4-Integrin and CXCR4 in Hematopoietic Stem/Progenitor Cell Mobilization
Concurrent Blockade of α4-Integrin and CXCR4 in Hematopoietic Stem/Progenitor Cell Mobilization
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DOI：
10.1002/stem.9
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Papayannopoulou, Thalia
中科院分区：
文献类型：
--
作者：
Bonig, Halvard;Watts, Korashon L.;Papayannopoulou, Thalia
已经证明了α 4整合素VLA-4和CXCR 4/SDF-1轴在动员中的重要作用，因此，这些途径可以被认为是在不使用细胞因子的情况下临床干细胞动员的合理靶点。单独的α 4-阻断（在人、猕猴和小鼠中）或在小鼠中α 4-整联蛋白的遗传消除提供了可再现的但适度的动员。类似地，用小分子拮抗剂阻断CXCR 4可动员所有三个物种中的造血干细胞，但至少在已建立的单次注射方案下，动员效率勉强足以用于临床目的。假设不同的分子靶点（α 4-整联蛋白与CXCR 4）可能允许累加动员效应，因此我们在猕猴中测试了α 4-整联蛋白阻断与抗功能抗体和CXCR 4阻断与小分子抑制剂AMD 3100的组合，或在小鼠中测试了条件性α 4-整联蛋白消融与AMD 3100的组合的疗效。动员至少是累加的。虽然α 4-阻断抗体的长期作用可能不适合临床动员，但未来小分子α 4-拮抗剂与AMD 3100联合使用可能会提供粒细胞集落刺激因子的替代方案。干细胞2009;27：836-837
The important contributions of the alpha 4 integrin VLA-4 and the CXCR4/SDF-1 axis in mobilization have been demonstrated and thereby, these pathways can be suggested as rational targets for clinical stem cell mobilization in the absence of cytokine use. alpha 4-blockade alone (in humans, macaques and mice), or genetic ablation of alpha 4-integrin in mice, provides reproducible, but modest mobilization. Similarly, CXCR4 blockade with small-molecule antagonists mobilizes hematopoietic stem cells in all three species, but at least with the established single-injection schedule, the mobilization efficiency is marginally sufficient for clinical purposes. Hypothesizing that the different molecular targets (alpha 4-integrin vs. CXCR4) might allow for additive mobilization effects, we therefore tested the efficacy of the combination of alpha 4-integrin blockade with anti-functional antibodies and CXCR4 blockade with the small-molecule inhibitor AMD3100 in macaques, or the combination of conditional alpha 4-integrin ablation and AMD3100 in mice. Mobilization was at least additive. While the prolonged effects of alpha 4-blocking antibodies may not be suitable for clinical mobilization, future availability of small-molecule alpha 4-antagonists in combination with AMD3100 could provide an alternative to granulocyte colony-stimulating factor. STEM CELLS 2009;27:836-837