Belmadani Abdelhak, Tran Phuong B, Ren Dongjun, Miller Richard J
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Neurosci. 2006 Mar 22;26(12):3182-91. doi: 10.1523/JNEUROSCI.0156-06.2006.
Many studies have shown that transplanted or endogenous neural progenitor cells will migrate toward damaged areas of the brain. However, the mechanism underlying this effect is not clear. Here we report that, using hippocampal slice cultures, grafted neural progenitor cells (NPs) migrate toward areas of neuroinflammation and that chemokines are a major regulator of this process. Migration of NPs was observed after injecting an inflammatory stimulus into the area of the fimbria and transplanting enhanced green fluorescent protein (EGFP)-labeled NPs into the dentate gyrus of cultured hippocampal slices. Three to 7 d after transplantation, EGFP-NPs in control slices showed little tendency to migrate and had differentiated into neurons and glia. In contrast, in slices injected with inflammatory stimuli, EGFP-NPs migrated toward the site of the injection. NPs in these slices also survived less well. The inflammatory stimuli used were a combination of the cytokines tumor necrosis factor-alpha and interferon-gamma, the bacterial toxin lipopolysaccharide, the human immunodeficiency virus-1 coat protein glycoprotein 120, or a beta-amyloid-expressing adenovirus. We showed that these inflammatory stimuli increased the synthesis of numerous chemokines and cytokines by hippocampal slices. When EGFP-NPs from CC chemokine receptor CCR2 knock-out mice were transplanted into slices, they exhibited little migration toward sites of inflammation. Similarly, wild-type EGFP-NPs exhibited little migration toward inflammatory sites when transplanted into slices prepared from monocyte chemoattractant protein-1 (MCP-1) knock-out mice. These data indicate that factors secreted by sites of neuroinflammation are attractive to neural progenitors and suggest that chemokines such as MCP-1 play an important role in this process.
许多研究表明，移植的或内源性神经祖细胞会向脑损伤区域迁移。然而，这种效应背后的机制尚不清楚。在此我们报告，利用海马脑片培养物，移植的神经祖细胞（NPs）会向神经炎症区域迁移，并且趋化因子是这一过程的主要调节因子。在将炎性刺激物注入海马伞区域并将增强型绿色荧光蛋白（EGFP）标记的NPs移植到培养的海马脑片的齿状回后，观察到了NPs的迁移。移植后3至7天，对照脑片中的EGFP-NPs几乎没有迁移倾向，并已分化为神经元和神经胶质细胞。相比之下，在注射了炎性刺激物的脑片中，EGFP-NPs向注射部位迁移。这些脑片中的NPs存活情况也较差。所使用的炎性刺激物是细胞因子肿瘤坏死因子-α和干扰素-γ、细菌毒素脂多糖、人类免疫缺陷病毒1型包膜蛋白糖蛋白120或表达β-淀粉样蛋白的腺病毒的组合。我们发现这些炎性刺激物会增加海马脑片多种趋化因子和细胞因子的合成。当将来自CC趋化因子受体CCR2基因敲除小鼠的EGFP-NPs移植到脑片中时，它们向炎症部位的迁移很少。同样，当将野生型EGFP-NPs移植到由单核细胞趋化蛋白-1（MCP-1）基因敲除小鼠制备的脑片中时，它们向炎症部位的迁移也很少。这些数据表明神经炎症部位分泌的因子对神经祖细胞具有吸引力，并提示诸如MCP-1等趋化因子在这一过程中起重要作用。
