摘要
目的：①建立大鼠骨髓间充质干细胞(bone mesenchymal stem cells, BMSCs)的分离、培养及基因转染技术；②筛选BMSCs、Noggin和脑源神经营养因子(brain-derived neurotrophic factor, BDNF)基因修饰的BMSCs、羟基红花黄色素A (hydroxysafflor yellow A, HSYA)口重复经颅磁刺激(repetitive transcranial magnetic stimulation, rTMS)等干预血管性痴呆(vascular dementia)大鼠的方法,结合大鼠空间记忆力和海马区血管内皮生长因子(vascular endothelial growth factor, VEGF)的表达分析其效果；③将大鼠海马区长时程增强(long-term potentiation, LTP)与BDNF和N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartic acid receptor, NMDAR)不同亚单位的表达结合,分析VaD大鼠空间记忆改善的机理。
方法：①提取大鼠长骨骨髓中的BMSCs,对其进行传代培养,通过MTT等方法计算细胞活力,通过流式细胞技术、成骨诱导和成脂诱导技术对其进行鉴定；②选取第3至第5代的BMSCs进行Noggin和BDNF基因转染,以VVestern blotting(?)勺方法检测BMSCs目的蛋白的表达；③采用2VO法制作VaD大鼠模型,实验动物随机分为正常组、假手术组、模型组、PBS组、生理盐水组、BMSCs组、Noggin修饰BMSCs组、BDNF修饰BMSCs组、HSYA组和rTMS组；④对造模后1周的VaD大鼠分别给予BMSCs移植、转染Noggin的BMSCs移植、转染BDNF的BMSCs移植、HSYA尾静脉注射2周和高频rTMS4周；⑤造模后5周行水迷宫实验检测各组大鼠的空间记忆功能,行LTP实验检测各组大鼠海马区的突触可塑性,以Western blotting的方法检测各组大鼠海马区VEGF、 BDNF、NR1、NR2A和NR2B的表达,以HE染色观察各组大鼠海马区的结构,以免疫组化的方法检测各组大鼠海马区VEGF和NR1的表达。
结果：①通过一般形态学的观察、流式细胞技术、成骨诱导和成脂诱导等鉴定方法显示,贴壁法分离、培养BMSCs可以有效达到纯化的目的；②通过荧光显微镜下观察和Western blotting法检测目的蛋白的表达,显示重组腺病毒Ad-GFP-Noggin和Ad-GFP-BDNF转染BMSCs,可使BMSCs高效表达Noggin和BDNF;③HE染色结果显示2VO法制作血管性痴呆模型,可以模拟人类血管性痴呆的病理表现,而各干预组均可使其病理变化得到改善；④水迷宫结果显不BMSCs移植、Noggin和BDNF转染BMSCs移植、HSYA和rTMS均可改善VaD大鼠的空间记忆功能,且Noggin和BDNF转染BMSCs组优于单纯给予BMSCs组；⑤Western blotting和免疫组化的结果显示,VaD模型组大鼠海马区VEGF表达轻度上调,HSYA和BDNF转染BMSCs可以显著上调VEGF的表达,其余各干预组增加VEGF表达的作用相对较小；⑥LTP结果显示,各干预组均明显优于VaD模型组,以Noggin、BDNF转染BMSCs组和rTMS组为著；⑦Western blotting和免疫组化的结果显示各干预组均可使海马区BDNF、NR1和NR2B的表达上调,以BDNF转染BMSCs组和rTMS组为著,而各组对NR2A均无显著影响。
结论：①贴壁筛选法分离、培养大鼠BMSCs,可获得纯度和活力均较高的BMSCs;②Noggin、BDNF对BMSCs的存活和分化具有重要意义,有望临床应用神经营养因子基因转染BMSCs治疗神经系统疾病；③BDNF基因修饰的BMSCs既能修复受损的记忆功能和突触效能,又可促进血管生成,其总体效果优于单纯的BMSCs移植和Noggin基因修饰的BMSCs移植,对VaD有良好的治疗前景；④HSYA可明显促进血管生成,rTMS可显著调节突触可塑性,有望将二者联合用于临床治疗VaD患者；⑤LTP的形成与BDNF和NMDAR有密切关系,其中NMDAR主要是NR1和NR2B的活化,而不是NR2A; BMSCs、Noggin基因转染BMSCs、BDNF基因转染BMSCs、HSYA和rTMS可能都是通过此途径而改善VaD大鼠的空间学习记忆能力。
Objecitive:①To establish the method of the isolation, cultivation and gene transfection of bone mesenchymal stem cells (BMSCs).②To evaluate the therapeutic effect of BMSCs, Noggin and brain-derived neurotrophic factor (BDNF) modified BMSCs, hydroxysafflor yellow A (HSYA) and repetitive transcranial magnetic stimulation (rTMS) on the vascular dementia (VaD) rats by the Morris water maze and the vascular endothelial growth factor (VEGF) expression in the hippocampus. To analyze the physiological and molecular mechanism of the learning and memory improvement, indicated by the long-term potentiation (LTP), the BDNF and different N-methyl-D-aspartic acid receptor (NMDAR) subunits expression in the hippocampus.
Method:①BMSCs were isolated from SD rats bone marrow and purified through adherence ability. These cells were identified as BMSCs by their phenotypical properties and their ability to differentiate into osteocyte and adipocyte.②Ad-GFP-Noggin gene and Ad-GFP-BDNF gene were transfected to the BMSCs. The target proteins were measured with Western blotting.③The rats were randomly divided into ten groups, including normal control, sham operation, VaD model, PBS, NS, BMSCs, Noggin modified BMSCs, BDNF modified BMSCs, HSYA and rTMS. The VaD model rats were made by two vessel occlusion (2VO) method.④BMSCs, Noggin modified BMSCs, BDNF modified BMSCs, HSYA(2weeks duration) and rTMS(4weeks duration) were administered in one week after the2VO.⑤The spatial learning and memory of all groups were measured by Morris water maze in five weeks after the operation. Then the CA3-to-CA1LTP were measured. The VEGF, BDNF, NR1, NR2A and NR2B expression in the hippocampus were measured with Western blotting. The pathologic changes were observed by hematoxylin and eosin stain. The VEGF and NR1expression in the hippocampus were also observed by immunohistochemistry.
Results:①The method that isolation and cultivation of BMSCs through the adherence ability could effectively purify the BMSCs, which identified by the morphology, flow cytometry, osteogenic differentiation and adipogenic differentiation. ②The BMSCs modified by Ad-GFP-Noggin and Ad-GFP-BDNF could express Noggin and BDNF respectively with high efficiency.③The2VO model could mimic the pathological features of vascular dementia in human, in which could be improved by BMSCs transplantation (modified with or without Noggin and BDNF), HS YA and rTMS.④All therapeutic groups could improve the spatial learning and memory of rats in the Morris Water Maze tests, and the improvement was greater in Noggin and BDNF modified BMSCs groups than that in BMSCs groups.⑤The VEGF expression in the hippocampus was slightly higher after2VO. HSYA and BDNF modified BMSCs transplantation could significantly up-regulate the VEGF expression in the hippocampus.⑥All the therapeutic groups could enhance the CA3-to-CA1LTP, especially the Noggin or BDNF modified BMSCs transplantation and the rTMS groups.⑦All the therapeutic groups could increase the BDNF, NR1and NR2B expression, but not NR2A, in the hippocampus, especially the BDNF modified BMSCs transplantation and the rTMS groups.
Conclusion:①BMSCs could be isolated and purified from rat bone marrow through the adherence ability and subculture.②Both Noggin and BDNF play a crucial role on the survival and differatiation of the BMSCs. The method of neurotrophic factors gene transfected BMSCs is a very hopeful therapeutic strategy in the nervous system diseases.③The BDNF modified BMSCs transplantation was proved to be better in improving the memory and synaptic efficacy, and promote the angiogenesis, compared with the BMSCs transplantation or Noggin modified BMSCs transplantation. Therefore the BDNF modified BMSCs transplantation is a promising therapeutic method in the treatment of VaD.④HSYA could promote the angiogenesis in the hippocampus, and rTMS could significantly enhance the synaptic plasticity, so combination HSYA and rTMS is worthwhile of applying in the treatment of VaD patients.⑤The formation of LTP is associated with BDNF, NR1and NR2B, but not NR2A, in the hippocampus. BMSCs (modified with or without Noggin and BDNF) transplantation, HSYA and rTMS improved the spatial learning and memory of the VaD rats through the BDNF-NMDAR (NR1/NR2B) dependent LTP.
引文
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