Neural Stem Cells Genetically Modified to Overexpress Cu/Zn-Superoxide Dismutase Enhance Amelioration of Ischemic Stroke in Mice

被引:60
作者
Sakata, Hiroyuki
Niizuma, Kuniyasu
Wakai, Takuma
Narasimhan, Purnima
Maier, Carolina M.
Chan, Pak H. [1 ]
机构
[1] Stanford Univ, Neurosurg Labs, Dept Neurosurg, Dept Neurol & Neurol Sci,Sch Med, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
copper/zinc-superoxide dismutase; ischemic stroke; neural stem cell; neuroprotection; FOCAL CEREBRAL-ISCHEMIA; PROTECTS VULNERABLE NEURONS; TRANSGENIC MICE; MUTANT MICE; STEM/PROGENITOR CELLS; OXIDATIVE STRESS; SELF-RENEWAL; INJURY; DAMAGE; TRANSPLANTATION;
D O I
10.1161/STROKEAHA.112.656900
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose-The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke. Methods-NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke. Results-Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through upregulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance compared with NSCs that were not genetically modified. Conclusions-Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke. (Stroke. 2012;43:2423-2429.)
引用
收藏
页码:2423 / +
页数:19
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