Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector
Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector
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DOI：
10.1038/sj.jcbfm.9600273
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发表时间：
2006-09
影响因子：
6.3
通讯作者：
Ming-Zhu Zhao;N. Nonoguchi;N. Ikeda;Takuji Watanabe;D. Furutama;Daisuke Miyazawa;H. Funakoshi;
中科院分区：
文献类型：
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作者：
Ming-Zhu Zhao;N. Nonoguchi;N. Ikeda;Takuji Watanabe;D. Furutama;Daisuke Miyazawa;H. Funakoshi;
闭塞性脑血管病导致脑缺血，导致神经功能缺损。在此，我们介绍了将间充质间质细胞（MSCs）和外肝细胞生长因子（HGF）基因与多突变的单纯疱疹病毒1型载体联合转染大鼠短暂性大脑中动脉闭塞（MCAO）模型的新策略。在MCAO后2h（超急性）或24h（急性）将基因转移的间充质干细胞移植到大鼠缺血脑内。行为测试显示，与磷酸盐缓冲盐水（PBS）治疗组和仅治疗MSCs组相比，hgf转移的MSCs （MSC-HGF）治疗组的神经功能缺损有显著改善。超急性治疗时，mscs - hgf组与PBS组在第3天的梗死面积有显著性差异，两种移植均在第14天的各组间有显著性差异。在超急性移植后，我们在治疗后第1天检测到MSC-HGF组缺血脑中HGF蛋白的表达较其他组丰富，并维持至少2周。此外，我们确定HGF表达的增加来源于基因修饰的MSCs中转移的HGF基因。与其他组相比，MSC-HGF组缺血边界区（IBZ）凋亡阳性细胞比例显著降低，IBZ皮层剩余神经元比例显著升高。目前的研究表明，联合治疗比单独MSC细胞治疗更有效，并且可以延长治疗时间窗口，从超急性期到急性期。
Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and exvivohepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate-buffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.