Song Shijie, Kong Xiaoyuan, Acosta Sandra, Sava Vasyl, Borlongan Cesar, Sanchez-Ramos Juan
James A Haley VAH Research Service, Tampa FL, USA.
Department of Neurology, University of South Florida, Tampa, FL, USA.
Restor Neurol Neurosci. 2016 Feb 24;34(3):415-31. doi: 10.3233/RNN-150607.
The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task.
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 μg/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.
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 Iba1 (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.
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.
总体目标是阐明粒细胞集落刺激因子（G-CSF）在海马依赖性学习任务中促进创伤性脑损伤恢复的细胞机制。
通过将来自转基因“绿色”小鼠的表达绿色荧光蛋白（GFP+）的骨髓细胞移植到C57BL/6小鼠中制备嵌合小鼠。两个月后，对动物右侧额顶叶皮质进行轻度控制性皮质撞击（CCI），随后连续3天给予G-CSF（100μg/kg）治疗。主要行为终点是在CCI前后（第7天和第14天）评估的放射状臂水迷宫（RAWM）中的表现。次要终点包括：a）在旋转圆柱体（转棒）上的运动表现，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，以及d）脑匀浆中神经营养因子（BDNF、GDNF）的测量。
G-CSF治疗导致在第1周时转棒上的表现显著更好，在第1周和第2周后在RAWM中的表现也显著更好。在G-CSF组中，CCI后2周发现的细胞变化包括海马新生神经元数量增加，以及双侧纹状体和额叶皮质中的星形细胞增生和小胶质细胞增生。在接受G-CSF治疗的动物中，与Iba1（小胶质细胞标志物）共标记的GFP+细胞在纹状体小胶质细胞中占很大比例，表明G-CSF有能力增加小胶质细胞向损伤部位的募集。在接受G-CSF治疗的小鼠中，由活化的小胶质细胞和星形胶质细胞产生的神经营养因子GDNF和BDNF增加。
G-CSF作为一种神经营养因子，可增加海马神经发生（或提高新生神经元的存活率），并激活星形胶质细胞和小胶质细胞。反过来，这些活化的胶质细胞释放大量细胞因子和神经营养因子，在一个尚不清楚的级联反应中促进大脑的修复反应。G-CSF还直接作用于骨髓来源的细胞，以增强小胶质细胞从循环单核细胞向CCI部位的募集。
