Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, Milano, Italy.
PLoS One. 2007 Apr 18;2(4):e373. doi: 10.1371/journal.pone.0000373.
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-beta1, Brain Derived Neurotrophic Factor and Stromal Derived Factor-1alpha, 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.
神经球衍生细胞（NC）含有神经干细胞、各种祖细胞和更分化的细胞，从新生 C57/BL6 小鼠中获得，并在伴有再灌注的局灶性缺血模型中输注，以研究以下问题：1）它们是否减少了缺血性损伤并恢复了脑功能；2）它们是否诱导了输注部位环境的变化；3）短暂缺血后继发的脑环境变化是否与 NC 作用相关。
方法/主要发现：NC 在 30 分钟大脑中动脉闭塞后 4 小时或 7 天经脑室输注。在缺血后 4 小时接受细胞输注的缺血小鼠中，与对照组和缺血后 7 天接受细胞输注的小鼠相比，旷场表现的损伤明显改善，神经元丢失明显减少，在缺血后 7-14 天。在相同实验条件下，输注鼠胎成纤维细胞无效。输注细胞分布的评估表明，它们从脑室迁移到实质，数量逐渐减少，但在 14 天内仍可观察到。在缺血后 7 天接受 NC 输注的小鼠和假手术小鼠中，只有在 24 小时才能观察到少量细胞，表明这些细胞在脑组织中的存活与缺血环境有关。在缺血后 4 小时接受 NC 输注的缺血小鼠中，胰岛素样生长因子-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衍生因子-1α等营养因子的 mRNA 表达以及小胶质细胞/巨噬细胞激活，与假手术组和缺血后 7 天接受细胞组相比，在 24 小时后增加。
结论/意义：NC 可减轻缺血再灌注损伤后的功能障碍和神经元损伤。有几条证据表明，NC 与缺血环境之间的相互作用对 NC 的保护作用至关重要。基于这些结果，我们提出，对缺血环境的旁观者控制可能是 NC 迅速恢复急性损伤脑功能的机制。
