Song Shijie, Kong Xiaoyuan, Acosta Sandra, Sava Vasyl, Borlongan Cesar V, Sanchez-Ramos Juan
James A Haley VAH, Research Service, 13000 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
Department of Neurology, University of South Florida, 13220 Laurel Drive, Tampa, FL 33612, USA.
Int J Mol Sci. 2017 Jul 2;18(7):1418. doi: 10.3390/ijms18071418.
Administration of the hematopoietic growth factor granulocyte-colony stimulating Factor (G-CSF) has been reported to enhance recovery from controlled cortical impact (CCI) in rodent models. G-CSF exerts actions in both the periphery (stimulation of hematopoiesis) and in the brain, where it serves as a neurotrophic factor, promoting neuronal survival and stimulating neural stem/progenitor cell proliferation in the hippocampus. In order to distinguish the direct CNS actions of G-CSF from its peripheral actions, experiments were designed to block the recruitment of peripheral monocytes to the site of the lesion produced by CCI. The selective C-C motif receptor 2 (CCR2) antagonist (RS504303) was co-administered with G-CSF for three days after CCI in a chimeric mouse previously transplanted with GFP-expressing (GFP+) blood stem-progenitor cells.
The drug significantly impaired infiltration of GFP+ bone marrow-derived cells to the frontal cortex and striatum without impeding recovery performance and hippocampal neurogenesis in the behavioral test, the Radial Arm Water Maze (RAWM). Administration of the CCR2 antagonist alone, without G-CSF, was effective in promoting recovery in RAWM. These results support the hypothesis that the direct action of G-CSF on neural cells, independent of its hematopoietic effects, is primarily responsible for enhanced recovery from CCI. In addition, this study confirms the importance of CCR2 and its ligand, monocyte chemotactic protein-1 (MCP-1), in mediating the inflammatory response following CCI.
据报道，在啮齿动物模型中，给予造血生长因子粒细胞集落刺激因子（G-CSF）可促进可控皮质撞击（CCI）损伤后的恢复。G-CSF在外周（刺激造血）和大脑中均发挥作用，在大脑中它作为一种神经营养因子，促进神经元存活并刺激海马体中神经干/祖细胞的增殖。为了区分G-CSF在中枢神经系统（CNS）的直接作用与其外周作用，设计了实验来阻断外周单核细胞向CCI所致损伤部位的募集。在一只先前移植了表达绿色荧光蛋白（GFP+）的血干细胞祖细胞的嵌合小鼠中，CCI术后连续三天将选择性C-C基序受体2（CCR2）拮抗剂（RS504303）与G-CSF联合给药。
该药物显著损害了GFP+骨髓来源细胞向额叶皮质和纹状体的浸润，但在行为测试——放射状臂水迷宫（RAWM）中并未妨碍恢复表现和海马体神经发生。单独给予CCR2拮抗剂（不使用G-CSF）在促进RAWM恢复方面是有效的。这些结果支持了这样的假说，即G-CSF对神经细胞的直接作用（独立于其造血作用）是CCI损伤后恢复增强的主要原因。此外，本研究证实了CCR2及其配体单核细胞趋化蛋白-1（MCP-1）在介导CCI后的炎症反应中的重要性。
