Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia.
Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia.
复制标题
在心脏骤停引起的全脑缺血大鼠模型中，骨髓间充质干细胞共过表达 BDNF 和 VEGF 增强神经保护功效。
DOI：
10.1038/cddis.2017.184
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Huang Z
中科院分区：
文献类型：
--
作者：
Zhou L;Lin Q;Wang P;Yao L;Leong K;Tan Z;Huang Z
心脏骤停诱导的全脑缺血损伤（CA-GCII）通常导致神经功能不良，缺乏有效的治疗。骨髓间充质干细胞（BMMSCs）通过诱导脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的表达，可能为神经系统疾病的治疗提供一种潜在的细胞基础疗法。为了进一步优化BMMSC的神经保护功效，在本研究中，我们衍生了共过表达BDNF和VEGF的BMMSC，并在大鼠模型中测试它们用于治疗CA-GCII。分别使用双顺反子穿梭载体pLVX-IRES-ZsGreen 1和pLVX-IRES-tdTomato产生表达大鼠BDNF外显子IV或VEGF-A的慢病毒。通过颈静脉注射刚从心脏骤停恢复的大鼠的BMMSC，所述BMMSC用BDNF和VEGF沿着与相应的荧光蛋白报道基因共过表达的工程化慢病毒共转导。然后对动物的神经功能缺陷进行评分，并在治疗后7天检查与植入相关的脑病理学和基因表达。我们证明了慢病毒载体转导的BMMSCs的锚定，其在海马和颞叶皮层共过表达BDNF和VEGF，沿着显著改善脑病理学，并改善移植后CA-GCII大鼠的神经功能表现。这些发现为将来在临床实践中进一步验证工程化BMMSCs用于治疗CA-GCII患者提供了概念证明。
Cardiac arrest-induced global cerebral ischemia injury (CA-GCII) usually leads to a poor neurological outcome without an effective treatment. Bone marrow-derived mesenchymal stem cells (BMMSCs) may provide a potential cell-based therapy against neurologic disorders through induction of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). To optimize the neuroprotective efficacy of BMMSCs further, in this study we have derived BMMSCs, which co-overexpress both BDNF and VEGF, and tested them for the treatment of CA-GCII in a rat model. Lentiviruses that express rat BDNF exon IV or VEGF-A were created using the bicistronic shuttle vectors of pLVX-IRES-ZsGreen1 and pLVX-IRES-tdTomato, respectively. BMMSCs that were co-transduced with the engineered lentiviruses with co-overexpression of both BDNF and VEGF along with corresponding fluorescent protein reporters were injected via jugular vein of rats that just recovered from a cardiac arrest. Animals were then scored for neurofunctional deficits and examined for brain pathology and gene expression relevant to the engraftment seven days after the treatments. We demonstrate that anchorage of lentiviral vector-transduced BMMSCs, which co-overexpressed both BDNF and VEGF in the hippocampus and temporal cortex along with significantly ameliorated brain pathology and improved neurofunctional performance in CA-GCII rats after transplantation. These findings provide a proof of concept for the further validation of engineered BMMSCs for the treatment of CA-GCII patients in clinical practice in the future.
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DOI：
10.1007/978-1-4939-0320-7_2
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Greenberg DA
通讯作者：
Greenberg DA
影响因子：
5.3
作者：
Calabrese F;Rossetti AC;Racagni G;Gass P;Riva MA;Molteni R
通讯作者：
Molteni R
影响因子：
5.3
作者：
Croll, SD;Ransohoff, RM;Wiegand, SJ
通讯作者：
Wiegand, SJ
影响因子：
158.5
作者：
Bunch, TJ;White, RD;Packer, DL
通讯作者：
Packer, DL
影响因子：
4.7
作者：
Koppel, Indrek;Tuvikene, Juergen;Timmusk, Tonis
通讯作者：
Timmusk, Tonis