Spine and Spinal Cord Institute, Department of Neurosurgery, Yonsei University College of Medicine, Seoul, South Korea.
Gene Ther. 2012 May;19(5):513-21. doi: 10.1038/gt.2011.137. Epub 2011 Oct 20.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the differentiation and function of hematopoietic cells. GM-CSF has been implicated in nervous system function. The goal of the present study was to understand the effects of hypoxia-induced GM-CSF on neural stem cells (NSCs) in a model of spinal cord injury (SCI). GM-CSF-overexpressing NSCs were engineered utilizing a hypoxia-inducible gene expression plasmid, including an Epo enhancer ahead of an SV promoter (EpoSV-GM-CSF). Cells were then subjected to hypoxia (pO(2), 1%) or a hypoxia-mimicking reagent (CoCl(2)) in vitro. The progression of time of GM-CSF expression was tracked in EpoSV-GM-CSF-transfected NSCs. Overexpression of GM-CSF in undifferentiated and differentiated NSCs created resistance to H(2)O(2)-induced apoptosis in hypoxia. NSCs transfected with EpoSV-GM-CSF or SV-GM-CSF were transplanted into rats after SCI to assess the effect of GM-CSF on NSC survival and restoration of function. Moreover, a significantly higher amount of surviving NSCs and neuronal differentiation was observed in the EpoSV-GM-CSF-treated group. Significant improvement in locomotor function was also found in this group. Thus, GM-CSF overexpression by the Epo enhancer in hypoxia was beneficial to transplanted NSC survival and to behavioral improvement, pointing toward a possible role for GM-CSF in the treatment of SCI.
粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 是一种造血细胞因子，可刺激造血细胞的分化和功能。GM-CSF 与神经系统功能有关。本研究的目的是了解缺氧诱导的 GM-CSF 对脊髓损伤 (SCI) 模型中神经干细胞 (NSC) 的影响。利用缺氧诱导基因表达质粒，包括 Epo 增强子和 SV 启动子（EpoSV-GM-CSF）工程改造 GM-CSF 过表达 NSC。然后将细胞置于体外低氧（pO(2)，1%）或缺氧模拟试剂（CoCl(2)）中。在 EpoSV-GM-CSF 转染的 NSCs 中跟踪 GM-CSF 表达的时间进程。未分化和分化的 NSCs 中 GM-CSF 的过表达可在低氧条件下抵抗 H(2)O(2)诱导的细胞凋亡。将 EpoSV-GM-CSF 或 SV-GM-CSF 转染的 NSCs 移植到 SCI 大鼠体内，以评估 GM-CSF 对 NSC 存活和功能恢复的影响。此外，在 EpoSV-GM-CSF 处理组中观察到存活的 NSCs 和神经元分化的数量显著增加。该组的运动功能也得到了显著改善。因此，Epo 增强子在低氧下的 GM-CSF 过表达有利于移植的 NSC 存活和行为改善，表明 GM-CSF 在 SCI 治疗中可能具有作用。
