GM-CSF Enhances Mobilization of Bone Marrow Mesenchymal Stem Cells via a CXCR4-Medicated Mechanism
GM-CSF Enhances Mobilization of Bone Marrow Mesenchymal Stem Cells via a CXCR4-Medicated Mechanism
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DOI：
10.1007/s13770-018-0163-5
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发表时间：
2019-02-01
影响因子：
3.6
通讯作者：
Choi, Byung Hyune
中科院分区：
文献类型：
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作者：
Kim, Jiyoung;Kim, Na Kyeong;Choi, Byung Hyune
目的：观察粒细胞-巨噬细胞集落刺激因子（GM-CSF）对大鼠骨髓间充质干细胞（MSCs）向外周血动员的影响。结果：GM-CSF给药后第1天，大鼠骨髓和外周血单个核细胞数量均迅速增加，第2天，骨髓单个核细胞数量增加，第3天，骨髓单个核细胞数量增加，第5天，骨髓单个核细胞数量增加。在BM中，该数量随时间逐渐降低，到第5天低于初始量，但在PB中维持在高水平直到第5天。GM-CSF给药第5天，PB中的集落形成单位成纤维细胞增加了10.3倍，但BM中的集落形成单位成纤维细胞减少。与GM-CSF相比，粒细胞集落刺激因子（G-CSF）刺激较低水平的MSC从BM动员到PB。免疫组化分析显示，GM-CSF诱导缺氧和蛋白水解微环境，并增加C-X-C趋化因子受体4型（CXCR 4）在BM中的表达。在体外向骨髓间充质干细胞中加入GM-CSF以剂量依赖性方式增加CXCR 4表达和细胞迁移。G-CSF和基质细胞衍生因子-1（SDF-1）在这些体外试验中显示出相似的结果。siRNA下调CXCR 4的表达可显著抑制GM-CSF和G-CSF诱导的MSC迁移，提示SDF-1与CXCR 4的相互作用参与了MSC迁移的机制。结论：GM-CSF是一种有效的动员骨髓间充质干细胞进入外周血的工具。
Background:This study was conducted to investigate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the mobilization of mesenchymal stem cells (MSCs) from the bone marrow (BM) into the peripheral blood (PB) in rats.Methods:GM-CSF was administered subcutaneously to rats at 50g/kg body weight for 5 consecutive days. The BM and PB of rats were collected at 1, 3, and 5days during the administration for analysis.Results:Upon GM-CSF administration, the number of mononuclear cells increased rapidly at day 1 both in the BM and PB. This number decreased gradually over time in the BM to below the initial amount by day 5, but was maintained at a high level in the PB until day 5. The colony-forming unit-fibroblasts were increased in the PB by 10.3-fold at day 5 of GM-CSF administration, but decreased in the BM. Compared to GM-CSF, granulocyte-colony stimulating factor (G-CSF) stimulated lower levels of MSC mobilization from the BM to the PB. Immunohistochemical analysis revealed that GM-CSF induced a hypoxic and proteolytic microenvironment and increased C-X-C chemokine receptor type 4 (CXCR4) expression in the BM. GM-CSF added to BM MSCs in vitro dose-dependently increased CXCR4 expression and cell migration. G-CSF and stromal cell derived factor-1 (SDF-1) showed similar results in these in vitro assays. Know-down of CXCR4 expression with siRNA significantly abolished GM-CSF- and G-CSF-induced MSC migration in vitro, indicating the involvement of the SDF-1-CXCR4 interaction in the mechanism.Conclusion:These results suggest that GM-CSF is a useful tool for mobilizing BM MSCs into the PB.