慢病毒介导人神经营养素-3基因修饰的神经干细胞移植治疗大鼠脑缺血的实验研究
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摘要
研究背景和目的中风是一类严重影响人类健康的疾病,尤其是缺血性脑血管病(ischemic cerebrovascular disease,ICD),造成中枢神经系统大量神经细胞缺失及神经网络受损,导致患者长期神经功能障碍。目前治疗缺血性中风的方法,临床上疗效比较确切的,只有超早期血管内治疗的方法,通过恢复脑血流来挽救缺血区濒临死亡的细胞。由于中风发生后神经细胞死亡进展迅速,大脑的再生能力相当有限,使得中风及相关问题的处理相当困难。基因治疗和干细胞移植,是近年来有关中风治疗研究的两个主要途径,旨在防止或减少缺血后神经细胞死亡的发生,以及刺激中枢神经系统内源性神经干细胞(neural stem cells,NSCs)增殖,或直接发挥“细胞替代”作用,为。ICD的治疗带来一线希望。
然而,中风发生后,内源性神经干细胞对脑组织修复的促进作用非常有限。有研究表明,大约80%新增殖的内源性神经干细胞会在6周内死亡,仅有0.2%的细胞缺失能得以替代。干细胞移植(包括神经干细胞胞、骨髓间充质干细胞等)后,一定程度上能改善脑缺血动物的神经功能,但是,其机理不十分明确。到现在止,多数研究者认为,干细胞移植是通过所谓的“bystandermechanism”而非直接“细胞替代”而发挥治疗作用。近年来,干细胞治疗脑血管病的研究的重点已转向刺激中枢神经系统内源性神经干细胞的增殖并防止其凋亡的方向上来。特别是神经干细胞已经被用作基因治疗的载体,可将治疗基因携带到病灶,通过治疗基因在缺血性损伤局部表达,来改变神经干细胞巢所处的微环境,即通过对所谓“bystander mechanism”机制的放大作用,来对内源性神经干细胞的增殖、分化及存活进行调控,有望为中风的治疗带来新的希望。
本课题研究目的是探讨人神经营养素-3(human neurotrophin-3,hNT-3)基因修饰的神经干细胞移植后,对缺血性脑损伤大鼠海马齿状回(dentategyrus,DG)和纹状体半暗带内源性神经前体细胞的增殖与分化的影响,以及对神经功能改善的治疗作用,探讨其可能的治疗机制,为脑缺血的干细胞治疗寻找新途径。
方法实验共分三部分。第一部分:从孕14天Sprague-Dawley(S-D)大鼠胚胎的脑组织分离出神经干细胞,采用无血清培养法,进行体外培养、扩增,并通过免疫荧光化学染色(巢蛋白)进行鉴定。取传至第5～6代神经干细胞,以1×10~5个细胞/500μl/孔接种于24孔板,分别按复感染指数(Multiplicities of infection,MOIs值)为0、1、5、10、15、20加入携带报告基因GFP的慢病毒载体(lentiviral vector-GFP,LV/GFP)稀释液,每一滴度加六孔,共六组。2～3天后于倒置荧光显微镜下观察各组GFP的表达效率,并在3天后进行神经干细胞球进行计数,观察LV/GFP对NSCs增殖的影响。并行流式细胞仪检测,得出各组NSCs的GFP阳性转染率。第二部分:重组表达hNT-3基因的载体质粒(pGC-E1/hNT3),并与2种辅助质粒(pHelper 1.0和pHelper 2.0)在包装细胞293T内应用Lipofectamine重组,构建成表达hNT3的慢病毒载体(lentiviral vector-hNT3,LV/hNT3)。并通过RT-PCR和Western-blot检测病毒载体的生物学活性。第三部分:雄性S-D大鼠建立脑缺血再灌注脑损伤模型,并随机分为三组。实验组用LV/hNT3转染5～6代NSCs,并在术后第七天,将NSCs-hNT3移植到大鼠纹状体半暗带。对照组移植普通NSCs或生理盐水。各组大鼠在细胞移植前后的不同时期进行运动功能和行为学检测评分,并取样检测细胞移植点NT-3及其受体TRKC的表达水平。应用免疫荧光染色方法对细胞移植2周后内源性神经前体细胞的增殖与分化进行检测。
结果第一部分:NSCs以悬浮细胞球方式生长,nestin染色阳性。转染GFP基因后,除MOI值为0的对照组外,2～3天后各孔均有GFP表达。MOI值从0增至10,细胞的阳性表达率逐渐提高(P＜0.05),MOI值为10的组能获得＞90%的转染率。但MOI值从10增至20,形成的神经干细胞球数目却逐渐减少(P＜0.05)。第二部分:细胞转染hNT-3基因2～3天后,细胞提取物RT-PCR检测阳性,阳性克隆基因测序比对证实载体构建正确,Western-blot检测进一步证实病毒载体转染转染细胞后具有生物学活性。第三部分:与对照组比较,hNT-3基因修饰的NSCs移植后能在缺血区迁移,在移植点能分泌较高水平的hNT-3蛋白(P＜0.001),并且TRKC基因表达水平增加(P＜0.01)。移植hNT-3基因修饰的NSCs,能增加缺血性脑损伤大鼠海马齿状回和纹状体半暗带的内源性神经前体细胞增殖(BrdU~+)和向神经元方向分化(DCX~+)(P＜0.05),并能促进大鼠神经功能(NSS评分)的改善(P＜0.05)。
结论(1)LV是将外源基因转入神经干细胞的理想载体。以MOI为10的滴度,LV可将外源基因高效转入神经干细胞内。(2)慢病毒介导转染神经营养素-3基因的神经干细胞移植后,能在缺血脑组织内迁移并分泌明显高于对照组水平的神经营养素-3蛋白。(3)神经营养素-3基因修饰的神经干细胞移植对缺血性脑损伤大鼠海马齿状回和纹状体半暗带内新增殖细胞的增殖、向神经元方向分化以及大鼠神经功能的改善有促进作用。特殊基因修饰的神经干细胞治疗脑缺血具有可行性。
Background and Objective:Ischemic stroke is a leading cause of long-term neurological disability due to extensive loss of neurons and their connections in demaged regions of the brain.Current therapy for ischemic stroke is limited to acute measures designed to restore perfusion and,at least experimentally,to protect ischemic cells from death in acute phase.Yet,the rapid course of neuronal death and the brain's limited regenerative capacity make treatment of stroke and related disorders difficult.One approach to this problem involves the administration of agents which target down stream mediators of pathways involved in delayed neuronal death.Another approach focuses on neural stem cells,which are found in the adult central nervous system through the process of neurogenesis and might be capable of replacing dying cells in the post-ischemic brain.
The efficacy of endogenous NSCs in promoting brain repair is limited,about 80%of migrating newborn neurons would die within 6 weeks,and only abpout 0.2%of demaged cells could be replaced via neurogenesis.Although transplantation of stem cells(such as NSCs and BMSCs) can bring neurological function improvement to animals with cerebral ischemia,more and more researcher think that transplantation of neural stem cells may protect the central nervous system from inflammatory damage through a 'bystander' mechanism that is alternative to cell replacement.Recently,efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult CNS.And NSCs have already been used as gene delivery tools for carrying therapeutic genes to disease tissues. Transplantation of modified NSCs may have promise in cell replacement therapy for stroke.
The study tested the hypothesis that transplantation of human neurotrophin-3 (hNT-3) over-expressing neural stem cells(NSCs) into rat striatum after a severe focal ischemia would have better functional recovery compared with controls,as well as promote proliferation and neuronal differentiation of the endogenous progenitor cells in the dentate gyrus(DG) of hippocampus and striatal penumbra of rats.We investigated the putative mechamism of modified NSCs transplantation to cerebral ischemia in order to find a new way for cell-based therapy.
Methods The study consisted of three parts.PartⅠNeural stem cells were extracted from rat embryonic brain(E14),then grown,expended and propagated in serum-free medium.Passage 5～6 neural stem cells were seeded at a density of 1×10~5/500μl/well in 24-well plates and exposed to lentiviral vector(LV) coding for GFP reporter gene(LV/GFP) at multiplicities of infection(MOIs) of 0,1,5,10,15,20 respectively.There were six groups totally,and each group had six wells seeded.The cells were incubated in a humidified atmosphere with 5%CO2 at 37℃.2～3 days later,the cells were observed under inverted fluorescence microscope.And 3 days later,neurospheres were counted followed by flow cytometer examination to get the percentage of transgene positive NSCs. PartⅡThe lentiviral vector(LV) coding for Flag-tagged hNT-3(LV/hNT3) gene was constructed by the co-transfection of 293T cells with transfer plasmid coding for hNT-3(pGC-E1/hNT-3) and two help plasmids(pHelper 1.0 and Helper 2.0) using Lipofectamine 2000.The hNT-3 mRNA code sequences within the transduced cells was subsequently tested by RT-PCR and sequencing,the biological activity of LV/hNT-3 was demonstrated by western-blot analysis of total proteins from hNT-3 producer cells.PartⅢNSCs,transduced by hNT-3 gene mediated by LV,were transplanted into the post-infarct brain striatum of adult rats 7 days after 2-h occlusion of the middle cerebral artery(MCAO).From 1 day before transplantation to 2 weeks after transplantation,Neurological Severity Scores(NSS) were calculated and the levels of neurotrophin-3 as well as TRKC in the graft sites were studied.Immunofluorencence staining was used to label NSCs-hNT3(Flag-positive) and newly proliferated endogenous cells (BrdU-positive and DCX-positive).
Results:PartⅠ7～8 days after isolated from rat embryonic brain,NSCs grew as free-floating nestin-positive neurospheres.2～3 days after GFP gene transduction,GFP-expressing cells cound be seen except in the control group, Over 90%cells were GFP-positive at 3 days after transduction by LV at MOI of 10.A significant dose-response was observed with increasing virus titer for MOI 0 to 10(P＜0.05),whereas the amount of neurospheres decrease with increased virus load for MOI 10 to 20(P＜0.05).PartⅡIn the predent study,correct hNT-3 mRNA expression was demonstrated by RT-PCR analysis of total RNAs from hNT-3 producer cells,and RT-PCR products were also sequenced and verified by NCBI blast analysis to be correct.Furthermora,the biological activity of LV/hNT-3 was demonstrated by western-blot analysis of total proteins from hNT-3 producer cells.PartⅢAfter transplantation,the NSCs-hNT3 survived the transplantation procedures could migrate in the ischemic area and express significantly higher levels of hNT-3 protein in the graft sites compared with controls(P＜0.001).And ischemic rats received modified cells had a significantly higher number of newly proliferated cells(BrdU positive) in both the hippocampal dentate gyrus(DG) ipsilateral to the lesion(P＜0.05) and striatal penumbra(P＜0.05).Of the Brdu-positive cells,over 90%in the DG and one third in the penumbra were immature neurons(DCX positive).Furthermore, transplantation of NSCs-hNT3 could bring better functional recovery compared with controls.
Conclusion(1) LV is an ideal vector for gene transduction and it can transduce a foreign gene into NSCs with high efficency of over 90%at the MOI of 10.(2) Therapeutic genes could be carried to disease tissues through transplantation of modified NSCs and express effectively.(3) Over-expression of hNT-3 in the ischemic area might promote the survival of newly proliferated cells and have values for enhancing functional recovery after stroke.
然而,中风发生后,内源性神经干细胞对脑组织修复的促进作用非常有限。有研究表明,大约80%新增殖的内源性神经干细胞会在6周内死亡,仅有0.2%的细胞缺失能得以替代。干细胞移植(包括神经干细胞胞、骨髓间充质干细胞等)后,一定程度上能改善脑缺血动物的神经功能,但是,其机理不十分明确。到现在止,多数研究者认为,干细胞移植是通过所谓的“bystandermechanism”而非直接“细胞替代”而发挥治疗作用。近年来,干细胞治疗脑血管病的研究的重点已转向刺激中枢神经系统内源性神经干细胞的增殖并防止其凋亡的方向上来。特别是神经干细胞已经被用作基因治疗的载体,可将治疗基因携带到病灶,通过治疗基因在缺血性损伤局部表达,来改变神经干细胞巢所处的微环境,即通过对所谓“bystander mechanism”机制的放大作用,来对内源性神经干细胞的增殖、分化及存活进行调控,有望为中风的治疗带来新的希望。
本课题研究目的是探讨人神经营养素-3(human neurotrophin-3,hNT-3)基因修饰的神经干细胞移植后,对缺血性脑损伤大鼠海马齿状回(dentategyrus,DG)和纹状体半暗带内源性神经前体细胞的增殖与分化的影响,以及对神经功能改善的治疗作用,探讨其可能的治疗机制,为脑缺血的干细胞治疗寻找新途径。
方法实验共分三部分。第一部分:从孕14天Sprague-Dawley(S-D)大鼠胚胎的脑组织分离出神经干细胞,采用无血清培养法,进行体外培养、扩增,并通过免疫荧光化学染色(巢蛋白)进行鉴定。取传至第5～6代神经干细胞,以1×10~5个细胞/500μl/孔接种于24孔板,分别按复感染指数(Multiplicities of infection,MOIs值)为0、1、5、10、15、20加入携带报告基因GFP的慢病毒载体(lentiviral vector-GFP,LV/GFP)稀释液,每一滴度加六孔,共六组。2～3天后于倒置荧光显微镜下观察各组GFP的表达效率,并在3天后进行神经干细胞球进行计数,观察LV/GFP对NSCs增殖的影响。并行流式细胞仪检测,得出各组NSCs的GFP阳性转染率。第二部分:重组表达hNT-3基因的载体质粒(pGC-E1/hNT3),并与2种辅助质粒(pHelper 1.0和pHelper 2.0)在包装细胞293T内应用Lipofectamine重组,构建成表达hNT3的慢病毒载体(lentiviral vector-hNT3,LV/hNT3)。并通过RT-PCR和Western-blot检测病毒载体的生物学活性。第三部分:雄性S-D大鼠建立脑缺血再灌注脑损伤模型,并随机分为三组。实验组用LV/hNT3转染5～6代NSCs,并在术后第七天,将NSCs-hNT3移植到大鼠纹状体半暗带。对照组移植普通NSCs或生理盐水。各组大鼠在细胞移植前后的不同时期进行运动功能和行为学检测评分,并取样检测细胞移植点NT-3及其受体TRKC的表达水平。应用免疫荧光染色方法对细胞移植2周后内源性神经前体细胞的增殖与分化进行检测。
结果第一部分:NSCs以悬浮细胞球方式生长,nestin染色阳性。转染GFP基因后,除MOI值为0的对照组外,2～3天后各孔均有GFP表达。MOI值从0增至10,细胞的阳性表达率逐渐提高(P＜0.05),MOI值为10的组能获得＞90%的转染率。但MOI值从10增至20,形成的神经干细胞球数目却逐渐减少(P＜0.05)。第二部分:细胞转染hNT-3基因2～3天后,细胞提取物RT-PCR检测阳性,阳性克隆基因测序比对证实载体构建正确,Western-blot检测进一步证实病毒载体转染转染细胞后具有生物学活性。第三部分:与对照组比较,hNT-3基因修饰的NSCs移植后能在缺血区迁移,在移植点能分泌较高水平的hNT-3蛋白(P＜0.001),并且TRKC基因表达水平增加(P＜0.01)。移植hNT-3基因修饰的NSCs,能增加缺血性脑损伤大鼠海马齿状回和纹状体半暗带的内源性神经前体细胞增殖(BrdU~+)和向神经元方向分化(DCX~+)(P＜0.05),并能促进大鼠神经功能(NSS评分)的改善(P＜0.05)。
结论(1)LV是将外源基因转入神经干细胞的理想载体。以MOI为10的滴度,LV可将外源基因高效转入神经干细胞内。(2)慢病毒介导转染神经营养素-3基因的神经干细胞移植后,能在缺血脑组织内迁移并分泌明显高于对照组水平的神经营养素-3蛋白。(3)神经营养素-3基因修饰的神经干细胞移植对缺血性脑损伤大鼠海马齿状回和纹状体半暗带内新增殖细胞的增殖、向神经元方向分化以及大鼠神经功能的改善有促进作用。特殊基因修饰的神经干细胞治疗脑缺血具有可行性。
Background and Objective:Ischemic stroke is a leading cause of long-term neurological disability due to extensive loss of neurons and their connections in demaged regions of the brain.Current therapy for ischemic stroke is limited to acute measures designed to restore perfusion and,at least experimentally,to protect ischemic cells from death in acute phase.Yet,the rapid course of neuronal death and the brain's limited regenerative capacity make treatment of stroke and related disorders difficult.One approach to this problem involves the administration of agents which target down stream mediators of pathways involved in delayed neuronal death.Another approach focuses on neural stem cells,which are found in the adult central nervous system through the process of neurogenesis and might be capable of replacing dying cells in the post-ischemic brain.
The efficacy of endogenous NSCs in promoting brain repair is limited,about 80%of migrating newborn neurons would die within 6 weeks,and only abpout 0.2%of demaged cells could be replaced via neurogenesis.Although transplantation of stem cells(such as NSCs and BMSCs) can bring neurological function improvement to animals with cerebral ischemia,more and more researcher think that transplantation of neural stem cells may protect the central nervous system from inflammatory damage through a 'bystander' mechanism that is alternative to cell replacement.Recently,efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult CNS.And NSCs have already been used as gene delivery tools for carrying therapeutic genes to disease tissues. Transplantation of modified NSCs may have promise in cell replacement therapy for stroke.
The study tested the hypothesis that transplantation of human neurotrophin-3 (hNT-3) over-expressing neural stem cells(NSCs) into rat striatum after a severe focal ischemia would have better functional recovery compared with controls,as well as promote proliferation and neuronal differentiation of the endogenous progenitor cells in the dentate gyrus(DG) of hippocampus and striatal penumbra of rats.We investigated the putative mechamism of modified NSCs transplantation to cerebral ischemia in order to find a new way for cell-based therapy.
Methods The study consisted of three parts.PartⅠNeural stem cells were extracted from rat embryonic brain(E14),then grown,expended and propagated in serum-free medium.Passage 5～6 neural stem cells were seeded at a density of 1×10~5/500μl/well in 24-well plates and exposed to lentiviral vector(LV) coding for GFP reporter gene(LV/GFP) at multiplicities of infection(MOIs) of 0,1,5,10,15,20 respectively.There were six groups totally,and each group had six wells seeded.The cells were incubated in a humidified atmosphere with 5%CO2 at 37℃.2～3 days later,the cells were observed under inverted fluorescence microscope.And 3 days later,neurospheres were counted followed by flow cytometer examination to get the percentage of transgene positive NSCs. PartⅡThe lentiviral vector(LV) coding for Flag-tagged hNT-3(LV/hNT3) gene was constructed by the co-transfection of 293T cells with transfer plasmid coding for hNT-3(pGC-E1/hNT-3) and two help plasmids(pHelper 1.0 and Helper 2.0) using Lipofectamine 2000.The hNT-3 mRNA code sequences within the transduced cells was subsequently tested by RT-PCR and sequencing,the biological activity of LV/hNT-3 was demonstrated by western-blot analysis of total proteins from hNT-3 producer cells.PartⅢNSCs,transduced by hNT-3 gene mediated by LV,were transplanted into the post-infarct brain striatum of adult rats 7 days after 2-h occlusion of the middle cerebral artery(MCAO).From 1 day before transplantation to 2 weeks after transplantation,Neurological Severity Scores(NSS) were calculated and the levels of neurotrophin-3 as well as TRKC in the graft sites were studied.Immunofluorencence staining was used to label NSCs-hNT3(Flag-positive) and newly proliferated endogenous cells (BrdU-positive and DCX-positive).
Results:PartⅠ7～8 days after isolated from rat embryonic brain,NSCs grew as free-floating nestin-positive neurospheres.2～3 days after GFP gene transduction,GFP-expressing cells cound be seen except in the control group, Over 90%cells were GFP-positive at 3 days after transduction by LV at MOI of 10.A significant dose-response was observed with increasing virus titer for MOI 0 to 10(P＜0.05),whereas the amount of neurospheres decrease with increased virus load for MOI 10 to 20(P＜0.05).PartⅡIn the predent study,correct hNT-3 mRNA expression was demonstrated by RT-PCR analysis of total RNAs from hNT-3 producer cells,and RT-PCR products were also sequenced and verified by NCBI blast analysis to be correct.Furthermora,the biological activity of LV/hNT-3 was demonstrated by western-blot analysis of total proteins from hNT-3 producer cells.PartⅢAfter transplantation,the NSCs-hNT3 survived the transplantation procedures could migrate in the ischemic area and express significantly higher levels of hNT-3 protein in the graft sites compared with controls(P＜0.001).And ischemic rats received modified cells had a significantly higher number of newly proliferated cells(BrdU positive) in both the hippocampal dentate gyrus(DG) ipsilateral to the lesion(P＜0.05) and striatal penumbra(P＜0.05).Of the Brdu-positive cells,over 90%in the DG and one third in the penumbra were immature neurons(DCX positive).Furthermore, transplantation of NSCs-hNT3 could bring better functional recovery compared with controls.
Conclusion(1) LV is an ideal vector for gene transduction and it can transduce a foreign gene into NSCs with high efficency of over 90%at the MOI of 10.(2) Therapeutic genes could be carried to disease tissues through transplantation of modified NSCs and express effectively.(3) Over-expression of hNT-3 in the ischemic area might promote the survival of newly proliferated cells and have values for enhancing functional recovery after stroke.
引文
1.张国瑾,赵增荣.国外脑血管疾病研究进展.北京:中国医药科技出版社,2000,177-97.
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