Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment
Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment
复制标题
DOI：
10.1371/journal.pone.0000373
复制
发表时间：
2007-04-18
期刊：
影响因子：
3.7
通讯作者：
De Simoni, Maria-Grazia
中科院分区：
文献类型：
--
作者：
Capone, Carmen;Frigerio, Simona;De Simoni, Maria-Grazia
背景。从新生 C57/BL6 小鼠中获得含有神经干细胞、各种祖细胞和更多分化细胞的神经球衍生细胞 (NC)，并将其注入局灶性缺血再灌注的小鼠模型中，以研究是否：1）它们减少了缺血性损伤并恢复了脑功能； 2）它们引起了注入环境的变化； 3)短暂性脑缺血引起的脑环境变化与NC作用相关。方法/主要发现。大脑中动脉闭塞30分钟后4小时或7天将NC注入脑室内。与对照组和7天时接受细胞的缺血小鼠相比，在4小时时接受细胞的缺血小鼠中，缺血后7-14天开放场表现的损伤显着改善，神经元损失显着减少。在相同的实验条件下输注小鼠胎儿成纤维细胞没有效果。对输注细胞分布的评估显示，它们从心室迁移到实质，数量逐渐减少，但可观察到长达 14 天。在7天接受NC的小鼠和假手术小鼠中，仅在24小时时才能观察到很少的细胞，表明这些细胞在脑组织中的存活与缺血环境有关。与假手术小鼠和7天接受细胞的小鼠相比，在NC输注4小时后治疗的缺血小鼠中，胰岛素生长因子-1、血管内皮生长因子-A、转化生长因子-β1、脑源性神经营养因子和基质源性因子-1α等营养因子的mRNA表达以及小胶质细胞/巨噬细胞活化在24小时内增加。结论/意义。 NC 可减少缺血/再灌注损伤后的功能障碍和神经元损伤。多项证据表明，NC 与缺血环境之间的相互作用对于 NC 保护作用至关重要。基于这些结果，我们提出，旁观者对缺血环境的控制可能是 NC 用来快速恢复急性损伤脑功能的机制。
Background. Neurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action. Methodology/Principal Findings. NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7-14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-beta 1, Brain Derived Neurotrophic Factor and Stromal Derived Factor-1 alpha, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d. Conclusions/Significance. NC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.