孟 锐,蔡思琦,姜春香,隆晓菁,张丽娟.全脑小胶质细胞分布与 C6 胶质瘤侵袭性研究[J].集成技术,2018,7(5):29-35
全脑小胶质细胞分布与 C6 胶质瘤侵袭性研究
The Relationship Between Distribution of Microglia in Cerebral Gliomaand Invasion of C6 Glioma
  
DOI:
中文关键词:  胶质瘤;小胶质细胞;时空异质性;C6 大鼠模型
英文关键词:glioma; microglia; spatiotemporal heterogeneity; C6 rat model
基金项目:国家 973 项目(2015CB755500)
作者单位
孟 锐 中国科学院深圳先进技术研究院 深圳 518055;中国科学院大学 北京 100049 
蔡思琦 中国科学院深圳先进技术研究院 深圳 518055;中国科学院大学 北京 100049 
姜春香 中国科学院深圳先进技术研究院 深圳 518055 
隆晓菁 中国科学院深圳先进技术研究院 深圳 518055 
张丽娟 中国科学院深圳先进技术研究院 深圳 518055 
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中文摘要:
      小胶质细胞是大脑胶质瘤的重要非肿瘤成分之一。胶质瘤和小胶质细胞的相互作用促进肿瘤生长。然而,小胶质细胞的时空异质性对胶质瘤生物学特性的影响仍不确定。该研究在 28 只 SD 大鼠脑组织中植入 C6 胶质瘤细胞的基础上建立大脑胶质瘤模型,研究肿瘤进展过程中小胶质细胞的分布 与肿瘤进展的关系。在模型建立后,首先在手术后第 7、9、12、14、16、18、22、23 和 24 天采用核磁共振进行 T2 加权成像扫描(T2WI),并选取肿瘤径线最大的层面测量肿瘤直径和平均信号强度。然后,牺牲实验动物,取全部脑组织制作切片以进行苏木精-伊红(Hematoxylin-Eosin,HE)染色和免疫 荧光染色。选取肿瘤径线最大 HE 染色图片分别于肿瘤内、肿瘤周围及肿瘤对侧脑区定义 9 个感兴趣区域;使用尺度不变特征变换算法来配准和融合 HE 染色图像与免疫荧光图像。最后,将 HE 切片上定义的感兴趣区域映射到免疫荧光染色图像,测量每个感兴趣区域内小胶质细胞的平均荧光强度,并分析平均荧光强度与 C6 胶质瘤成瘤时间的相关关系。结果显示,肿瘤区域的平均荧光强度明显大于 其他感兴趣区域中的平均荧光强度(P<0.001),且平均荧光强度随着成瘤时间和肿瘤直径的增加而增加,分别拟合于二次曲线和线性函数;肿瘤平均荧光强度与平均信号强度呈显著正相关(P<0.001)。研究结果表明,C6 胶质瘤的进展在肿瘤内和非肿瘤的全脑范围内触发了小胶质细胞的加速趋化,在全脑范围内监测小胶质细胞分布的时空异质性可为靶向微环境的胶质瘤治疗提供参考依据。
英文摘要:
      Microglia is one of the important non-neoplastic elements of cerebral glioma. The interaction of glioma and microglia promotes tumor progression. However, the spatiotemporal heterogeneity of the microglia in the context of glioma remains uncertain. In this study, cerebral glioma model was built with C6 cell implantation in 28 SD rats to investigate the distribution of microglia during the tumor progression. T2 weighted magnetic resonance imaging (T2WI) was conducted at the post-operative day 7, 9, 12, 14, 16, 18, 22, 23 and 24 after the model built-up, after which the Hematoxylin-Eosin (HE) and immunofluorescent staining of the brain tissue were prepared. Nine regions of interest (ROI) were defined within the tumor, as the peritumoral and the contralesional areas on the HE sections with the largest tumor expansion. Scale-invariant feature transform (SIFT) algorithm was used to register and fuse the HE-immunofluorescent image pairs. ROIs defined on the HE sections were then translated to the immunofluorescence images. The averaged signal intensity was measured on the T2WI image with the largest tumor diameter. Mean density (MD) of the microglia in the ROIs were measured for each ROI and plotted with the time after C6 cell implantation. It can be observed that MD in the tumor ROI was significantly larger than that of the rest ROIs (P<0.001). MD increased with time and diameter that best fit to binomial and linear functions, respectively, for all the ROIs with a more precipitous inclination in the tumor MD. The average signal intensity of the ROIs on T2WI were also found positively correlated with the tumor MD. These findings indicate that tumor formation of C6 glioma triggers extensive microglia activation in the tumor and the non-neoplastic brain tissue, necessitating the assessment of microglia in both the local and global scales in performing the aggressiveness characterization and treatment trials targeting microenvironment of cerebral glioma.
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