Roles of Microglia In Developing brain functions

小胶质细胞在大脑功能发育中的作用

• 批准号: 09680774
• 负责人: SAWADA Makoto
• 金额: $ 1.98万
• 依托单位: Fujita Health University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680774/
• 关键词: microglia; gene transfection; brain-specific; brain development; brain function

Microglia, macrophage-like cells in the brain, are multi-functional cells. I found that microglia had a specific affinity to the brain but macrophages did not. When fluorescent-labeled microglial cells were injected into the aorta of an adult male rat, many fluorescent cells were observed in the brain and few were seen in the liver. These results suggest that microglia have a specific affinity and the ability to migrate to the brain. To determine whether an artificially modified gene could be transferred into brain using our novel technique, microglia were transected with a lacZ gene expression vector and were injected into the aorta of rats. When the brain sections were stained with X-gal, many blue cells were observed thoughout the brains prepared from rats injected with the cells carrying a lacZ gene expression vector. The activity of b-galactosidase was detected in the brain sections from these rats. Next, we compared migration of systemically injected microglia into normal brain vs. ischemic brain using a model of ischemic hippocampal lesion. Microglia were injected intra-arterially into Mongolian gerbils subjected to ischemia reperfusion neuronal injury. Delayed death of pyramidal neurons was confirmed by conventional histological analysis and dUTP nick end labeling (TUNEL) method. Clusters of dye-tagged cells migrating into the hippocampal ischemic lesions were confirmed histochemically to be microglia. Peripherally7 injected microglia exhibit specific affinity for ischemic brain lesions and does not exacerbate ischemic neuronal injury in the present model. Rather we found protective effects of exogenous microglia on delayed death of pyramidal neurons. Therefore, we suggest that microglia may have a potential to be used as a piggy-back ride to deliver therapeutic genes and/of drugs for CNS repair following transitory global ischemic insult.

小胶质细胞是大脑中的巨噬细胞样细胞，是多功能细胞。我发现小胶质细胞对大脑有特殊的亲和力，而巨噬细胞没有。将荧光标记的小胶质细胞注射到成年雄性大鼠的主动脉中，在大脑中观察到许多荧光细胞，在肝脏中观察到很少。这些结果表明，小胶质细胞具有特定的亲和力和迁移到大脑的能力。为了确定是否可以使用我们的新技术将人工修饰的基因转移到大脑中，用lacZ基因表达载体横切小胶质细胞，并注射到大鼠的主动脉中。当用X-gal对脑切片进行染色时，在从注射了携带lacZ基因表达载体的细胞的大鼠制备的脑中观察到许多蓝色细胞。在这些大鼠的脑切片中检测b-半乳糖苷酶的活性。接下来，我们使用缺血性海马损伤模型比较了全身注射的小胶质细胞向正常脑与缺血脑的迁移。将小胶质细胞动脉内注射到缺血再灌注神经元损伤的蒙古沙土鼠中。常规组织学分析和dUTP缺口末端标记（TUNEL）法证实锥体神经元的延迟性死亡。迁移到海马缺血性病变的染料标记的细胞簇被证实是小胶质细胞。外周注射的小胶质细胞对缺血性脑损伤表现出特异性亲和力，并且在本模型中不会加剧缺血性神经元损伤。相反，我们发现了外源性小胶质细胞对锥体神经元延迟死亡的保护作用。因此，我们认为，小胶质细胞可能有潜力被用来作为一个背负式乘坐提供治疗基因和/或药物的中枢神经系统修复后，短暂的全球缺血性损伤。

项目成果

Makoto Sawada: "Pathophysidogical significance of cytokine network in the brain" Brain and Biodifence (Oomura,Y and Hori,T eds.). 217-228 (1998)

Makoto Sawada：“大脑中细胞因子网络的病理生理学意义”Brain and Biodifence（Oomura，Y 和 Hori，T eds.）。

Suzumura,A.,Ito,A., Yoshikawa,M., Sawada,M.: "Ibudilast suppresses TNF alpha production by glial cells functioning mainly as type "III" phosphodiesterase inhibitor in the CNS."Brain Res.. 837. 203-212 (1999)

Suzumura,A.、Ito,A.、Yoshikawa,M.、Sawada,M.：“Ibudilast 抑制神经胶质细胞产生 TNF α，主要在中枢神经系统中充当“III”型磷酸二酯酶抑制剂。”Brain Res.. 837. 203

Takeuchi,A., Isobe,K., Miyaishi,O., Sawada,M., Fan,Z.H., Nakashima,I., Kiuchi,K.: "Microglial NO induces delayed neuronal death following acute injury in the striatum."Eur J Neurosci. 10. 1613-1620 (1998)

Takeuchi,A.、Isobe,K.、Miyaishi,O.、Sawada,M.、Fan,Z.H.、Nakashima,I.、Kiuchi,K.：“小胶质细胞 NO 在纹状体急性损伤后诱导延迟性神经元死亡。”Eur

F.Imai: "Migration activity of microglia and macrophage into ratbrain" Neuroscince Letters. 237. 49-52 (1997)

F.Imai：“小胶质细胞和巨噬细胞向鼠脑的迁移活动”《神经科学快报》。

Makoto Sawada: "IL-10 inhibits both production of cytokines and expression of cytokine receptors in microglia"J. Neurochem.. (in press). (1999)

Makoto Sawada：“IL-10 抑制小胶质细胞中细胞因子的产生和细胞因子受体的表达”J.