Granulocyte-colony stimulating factor promotes brain repair following traumatic brain injury by recruitment of microglia and increasing neurotrophic factor expression
Granulocyte-colony stimulating factor promotes brain repair following traumatic brain injury by recruitment of microglia and increasing neurotrophic factor expression
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DOI：
10.3233/rnn-150607
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发表时间：
2016-01-01
影响因子：
2.8
通讯作者：
Sanchez-Ramos, Juan
中科院分区：
文献类型：
--
作者：
Song, Shijie;Kong, Xiaoyuan;Sanchez-Ramos, Juan
目的：阐明G-CSF促进海马区依赖学习任务中创伤性脑损伤恢复的细胞机制。方法：将表达绿色荧光蛋白(GFP+)的转基因小鼠的骨髓细胞移植到C57BL/6小鼠体内，制备嵌合体小鼠。两个月后，动物对右侧额顶皮质进行轻度受控皮质撞击(CCI)，然后给予G-CSF(100[kg/kg)治疗，连续3天。主要的行为终点是在CCI前和CCI后(第7天和第14天)在放射状臂水迷宫(RAWM)上进行的评估。次要终点包括a)旋转圆柱体上的运动表现(Rotarod)，b)小胶质细胞和星形胶质细胞反应的测量，c)海马神经发生，d)脑匀浆中神经营养因子(BDNF，GDNF)的测量。结果：G-CSF治疗后1周旋转圆柱体上的运动表现明显好于1周后的rotod，1周后和2周后的rwm。CCI后2周，G-CSF组大鼠双侧海马区新生神经元增多，双侧纹状体和额叶皮质星形胶质细胞增多，小胶质细胞增多。在G-CSF处理的动物中，与IBAL(小胶质细胞标记物)共同标记的GFP+细胞构成了纹状体小胶质细胞的相当大比例，表明G-CSF有能力增加小胶质细胞在损伤部位的募集。结论：G-CSF是一种神经营养因子，可促进海马神经发生(或增强新生神经元的存活)，激活星形胶质细胞和小胶质细胞。反过来，这些激活的胶质细胞释放过多的细胞因子和神经营养因子，在一种鲜为人知的级联反应中，有助于大脑的修复反应。G-CSF还直接作用于骨髓来源的细胞，促进小胶质细胞从循环单核细胞向CCI部位募集小胶质细胞。
Purpose: The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task.Methods: Chimeric mice were prepared by transplanting bone marrow cells that express green fluorescent protein (GFP+) from a transgenic "green" mice into C57BL/6 mice. Two months later, the animals sustained mild controlled cortical impact (CCI) to the right frontal-parietal cortex, followed by G-CSF (100 [kg/kg) treatment for 3 consecutive days. The primary behavioral end-point was performance on the radial arm water maze (RAWM) assessed before and after CCI (days 7 and 14). Secondary endpoints included a), motor performance on a rotating cylinder (rotarod), b) measurement of microglial and astroglial response, c) hippocampal neurogenesis, and d) measures of neurotrophic factors (BDNF, GDNF) in brain homogenates.Results: G-CSF treatment resulted in significantly better performance on the rotorod at one week, and in the RAWM after one and two weeks. The cellular changes found 2 wks after CCI in the G-CSF group included increased numbers of hippocampal newborn neurons as well as astrocytosis and microgliosis in striatum and frontal cortex on both sides of brain. GFP+ cells that co-labeled with Ibal (microglial marker) comprised a significant proportion of striatal microglia in G-CSF treated animals, indicating the capacity of G-CSF to increase microglial recruitment to the site of injury. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF treated mice.Conclusions: G-CSF serves as a neurotrophic factor that increases hippocampal neurogenesis (or enhances survival of new-born neurons), and activates astrocytes and microglia. In turn, these activated glia release a plethora of cytokines and neurotrophic factors that contribute, in a poorly understood cascade, to the brain's repair response. G-CSF also acts directly on bone marrow-derived cells to enhance recruitment of microglia to the site of CCI from circulating monocytes to the site of CCI.