未成熟脑缺血损伤中影响神经干细胞微环境的因素及其作用途径
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摘要
【目的】神经干细胞(neural stem cell,NSC)微环境是调控神经干细胞增殖分化和自我更新的关键。目前对未成熟脑缺血性损伤中影响神经干细胞微环境的因素及其作用途径知之甚少。本课题通过研究未成熟脑缺血后神经干细胞的增殖分化及其微环境的相关变化,探讨缺血性损伤影响神经干细胞增殖分化的作用途径,并通过对血管内皮细胞分泌因子影响神经干细胞增殖分化的研究,进一步阐明其影响神经干细胞微环境的信号通路。此外,通过研究碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)干预对未成熟脑缺血后神经新生的作用,为早产儿脑损伤的治疗探索新的途径。
【方法】一.采用3日龄新生SD大鼠96只,随机分为实验组和对照组。实验组分离并结扎双侧颈总动脉,制备脑缺血模型;对照组仅分离,不结扎。两组大鼠分别于术后24h、4d、7d、14d处死取脑:1.采用免疫荧光染色方法,观察缺血对脑室下区(subventricular zone,SVZ)不同时点神经干细胞新生和增殖分化的影响;2.利用基因芯片技术,分析SVZ缺血后基因表达的变化,寻找缺血性损伤调控SVZ微环境变化的信号通路;3.采用real-time PCR、Western blot方法分别从基因和蛋白水平对发现的信号分子进行验证。
二.应用transwell共培养系统,建立3日龄新生SD大鼠SVZ脑片培养模型,随机分为三组:共培养组(血管内皮细胞+脑片)、共培养+siRNA组(血管内皮细胞+脑片+VEGF siRNA)和对照组(仅培养脑片)。其中血管内皮细胞采用ATCC鼠脑微血管内皮细胞株(bEnd.3,No.CRL-2299~(TM)),siRNA干扰采用脂质体转染法。脑片分别培养至第4d、7d、10d:1.采用免疫荧光染色的方法,观察血管内皮细胞分泌因子对脑片中神经干细胞增殖,及其向不同功能神经细胞分化的影响;2.通过基因芯片技术,分析在此过程中血管新生与神经新生相关基因表达的变化,探讨血管内皮细胞影响神经干细胞增殖分化的作用途径与机制,并采用real-time PCR方法对关键信号分子进行验证。
三.通过结扎3日龄新生SD大鼠双侧颈总动脉方法制备脑缺血模型后,随机分为治疗组(54只)和非治疗组(54只)。治疗组给予bFGF(10ng/g)侧脑室注射,非治疗组注射2μl生理盐水。另取54只3日龄新生SD大鼠作为假手术对照组(仅分离双侧颈总动脉,不结扎,不给予药物)。三组大鼠分别于术后第4d、7d、14d获取脑组织标本,采用免疫荧光双标、Western blot和real-time PCR的方法,观察三组大鼠不同时点SVZ巢蛋白(Nestin)、NeuN、胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)和少突胶质细胞NG2蛋白及其mRNA的表达变化,研究bFGF对神经干细胞新生和增殖分化的作用。
【结果】一.未成熟脑缺血性损伤后:1.脑组织病理切片可见SVZ神经细胞变性、坏死,细胞层次紊乱、排列松散,部分神经细胞固缩、胞浆深染、核浓缩,结构不清,以术后第4d损伤最重;2.免疫荧光标记结果显示SVZ新生细胞显著增加,包括神经干细胞(BrdU+/Nestin+)、神经元(BrdU+Tuj1+)、星形胶质细胞(BrdU+/GFAP+)和少突胶质细胞(BrdU+/O4+)数目均较对照组增加(P＜0.01),7d达高峰;3.基因芯片分析发现,与缺血后SVZ神经干细胞增殖分化相关的基因主要涉及VEGF、TGF-β1两条信号通路,定量分析结果显示VEGF、TGF-β1 mRNA和蛋白表达在缺血后均增加,7d达高峰,与对照组比较差异有统计学意义(p＜0.01)。
二.血管内皮细胞对未成熟脑神经干细胞的影响:1.共培养组神经干细胞(Nestin+)明显增加,在共培养7d达高峰,并且神经元(Tuj1+)、星形胶质细胞(GFAP+)和少突胶质细胞(O4+)数量亦增加,在共培养10d达高峰,与对照组和共培养+siRNA组相比,差异显著(P＜0.01)。2.与血管和神经新生相关的基因表达谱变化显示,共培养组有112个基因表达较对照组2倍以上升高,给予siRNA干预后,这112个上调的基因中有81个表达呈2倍以上降低。利用基因芯片显著性分析方法(significance analysis of microarray,SAM)筛选具有显著性表现的基因,并利用KEGG数据库将这些差异表达基因按照信号通路进行映射,发现显著性表现的基因主要涉及Notch和Pten信号通路,这两条信号通路与血管新生和神经干细胞增殖分化的调控有关。采用real-time PCR方法对这两条通路中主要基因进行验证,得到与芯片数据一致的结果。
三.未成熟脑缺血损伤后给予bFGF干预组:1.SVZ病理改变较对照组明显减轻;2.SVZ各种新生细胞(BrdU+)数量均较对照组显著增加,其中新生神经干细胞(BrdU+/Nestin+)在7d达高峰,而新生的神经元(BrdU+/NeuN+)、星形胶质细胞(BrdU+/GFAP+)和少突胶质细胞(BrdU+/NG2+)在14d达高峰,与非干预缺血组相比,差异均有显著意义(P＜0.01);3.Nestin蛋白和mRNA表达都在7d达高峰,NeuN、GFAP和NG2的蛋白和mRNA表达均在14d达高峰,与非干预缺血组相比,差异均有显著意义(P＜0.01)。
【结论】1.缺血促进未成熟脑SVZ神经干细胞的增殖及其向功能神经细胞的分化;2.VEGF和TGF-β信号通路参与调控缺血后神经干细胞的增殖分化,是缺血性损伤影响未成熟脑神经干细胞微环境的重要途径;3.血管内皮细胞分泌的可溶性细胞因子和对血管新生相关基因的抑制可影响神经干细胞的微环境,调节神经干细胞的增殖和分化;4.血管内皮细胞与神经干细胞的相互作用涉及多条通路,主要与Notch和Pten信号通路有关;5.bFGF干预可促进未成熟脑缺血后的神经新生,可能有助于缺血性损伤后的神经修复。
Objectives:Neural stem cell niche is a key factor to regulate the self-renewal, proliferation and differentiation of neural stem cells.However,little is known about how ischemia affects the neural stem cell niche in the premature brain.In order to clarify the mechanisms how ischemia effect on the neurogensis in the premature brain, we observed the proliferation and differentiation of neural stem cells and the changes of neural stem cell niche in a 3-day-old rat model following brain ischemia in this study.Furthermore,we elucidated the pathways which related to the neural stem cell niche through observing the effects of soluble factors secreted by vascular endothelial cells on proliferation and differentiation of neural stem cells.Besides,the effect of basic fibroblast growth factor(bFGF) on the proliferation and differentiation of neural stem cells after brain ischemia were investigated.The study will provide novel evidence for intervention of ischemic premature brain injury.
Methods:Part 1.The bilateral common carotid artery of rats was occluded to prepare the premature brain ischemia models.Proliferating cells were labeled by bromodeoxyuridine(BrdU) through intraperitoneal injection.By immunfluorescence staining,we observed the proliferation and differentiation of neural stem cells in the subventricular zone(SVZ) at 24h,4d,7d,and 14d after ischemic injury.And by used cDNA microarry chip,we monitored the changes of genes expression profile after brain ischemia.The significant change genes were testified by real-time quantitative polymerase chain reaction(PCR) and Western blot analysis.Part 2.SVZ brain slices of 3-day-old SD rats were cultured in vitro,they were divided into 3 groups randomly, named co-culture group(co-culture with vascular endothelial cells),co-culture and siRNA group(co-culture with vascular endothelial cells and siRNA) and control group(only culture brain slices),respectively.A mouse vascular endothelial cell line (bEnd.3,No.CRL-2299~(TM)) was used in the co-culture.RNA interference for knock-down VEGF gene expression was synthesized and transfection by liposome methods.At 4d,7d,and 10d of cultured,the proliferation and differentiation of neural stem cells in the brain slices were detected by immunfluorescence stain. Synchronously,the changes of genes involved neurogenesis and angiogenesis were analyzed by GeneChip and the relative signal pathways were further confirmed by real-time PCR.Part 3.One hundred and eight 3-day-old SD rats with brain ischemia were used in this experiment and half of them were received bFGF 10ng/g through lateral ventricles injection.Besides,fifty four 3-day-old SD rats without brain ischemia were used as normal control.Proliferating cells in brain were labeled by BrdU through intraperitoneal injection in a pulsed or a cumulative protocol.Rats were killed at 4d,7d,and 14d after operation,and the proliferation and differentiation of neural stem cells in the SVZ were observed by immunfluorescence assays,real-time PCR and Western blot analysis to evaluate the impact of bFGF on bain injury repair.
Results:Part 1:(1) There were cerebral edema widely;neuronal cells necrosis and focal cerebromalacia formation in the ischemic rats.These damages were the most serious at the 4th day after the operation.(2) In brain ischemic rats, BrdU+/Nestin+ cells in the SVZ were significantly increased at all four time points and more neural stem cells differentiated into neurons,astrocytes,and oligodendrocytes,compared with the rats without brain ischemia(P＜0.01).(3) GeneChip analysis showed a 3- to 10-fold increase in the mRNA expression of vascular endothelial growth factor(VEGF),transforming growth factor-beta (TGF-beta),and their receptors in the brain SVZ of ischemic rats,compared with that of without ischemic rats.PCR and Western blot analyses also confirmed these results. The data indicated that vascular endothelial growth factor and transforming growth factor-beta might be two important factors that involved post-ischemic neural stem cell proliferation and differentiation.Part 2:(1) The positive stain cells of Nestin, Tuj1,GFAP and O4 in brain slices were significantly increased in the co-culture group,compared with that in the control group(P＜0.01).But,when VEGF siRNA was added into the co-culture all these four type cells were decreased markedly (P＜0.01 vs the control group and co-culture group).(2) GeneChip analysis showed that the expressions of 112 genes were up-regulated more than 2-fold,however, among them 81 genes were down-regulated more than 2-fold after administration with VEGF siRNA.(3) Analyzed by "significance analysis of microarray" software,we found these noticeable altered genes were classified into notch and pten signal pathways on the ground of KEGG database,and these changes were further confirmed by real-time PCR assayes.Part 3:(1) The brain pathological damages in ischemic rats described in part 1 were alleviative in bFGF group.(2) Treatment with bFGF significantly increased the number of new cells(BrdU positive stain) in the SVZ at all three time points(P＜0.01).The new neural stem cells(BrdU/Nestin double positive cells) were peaked at 7d after operation,and amount in the bFGF group was more than that in the control group(P＜0.01).While,the new neurons(BrdU/NeuN double positive cells),astrocytes(BrdU/GFAP double positive cells),and oligodendrocytes(BrdU/NG2 double positive cells) were peaked at 14d.Treatment with bFGF significantly enhanced the number of these three group cells at all three time points(P＜0.01).Moreover,Real-time PCR and Western blot assay confirmed these results.
Conclusion:1.Ischemia induced the proliferation and differentiation of neural stem cells in the SVZ,which involved vascular endothelial growth factor and transforming growth factor-beta pathways.2.The soluble factors secreted by vascular endothelial cells enhance the proliferation and differentiation of neural stem cells in the SVZ.Moreover,inhibition of the expression of genes for angiogenesis attenuated the efficacy of vascular endothelial cells on neural stem cells.The effects of vascular endothelial cells on the neurogenesis were involved into many pathways,among them notch and pten signal pathways were important.3.bFGF stimulated the proliferation and differentiation of neural stem cells in neonatal rats after ischemic brain injury, which maybe is helpful for the neural repair after ischemia.
【方法】一.采用3日龄新生SD大鼠96只,随机分为实验组和对照组。实验组分离并结扎双侧颈总动脉,制备脑缺血模型;对照组仅分离,不结扎。两组大鼠分别于术后24h、4d、7d、14d处死取脑:1.采用免疫荧光染色方法,观察缺血对脑室下区(subventricular zone,SVZ)不同时点神经干细胞新生和增殖分化的影响;2.利用基因芯片技术,分析SVZ缺血后基因表达的变化,寻找缺血性损伤调控SVZ微环境变化的信号通路;3.采用real-time PCR、Western blot方法分别从基因和蛋白水平对发现的信号分子进行验证。
二.应用transwell共培养系统,建立3日龄新生SD大鼠SVZ脑片培养模型,随机分为三组:共培养组(血管内皮细胞+脑片)、共培养+siRNA组(血管内皮细胞+脑片+VEGF siRNA)和对照组(仅培养脑片)。其中血管内皮细胞采用ATCC鼠脑微血管内皮细胞株(bEnd.3,No.CRL-2299~(TM)),siRNA干扰采用脂质体转染法。脑片分别培养至第4d、7d、10d:1.采用免疫荧光染色的方法,观察血管内皮细胞分泌因子对脑片中神经干细胞增殖,及其向不同功能神经细胞分化的影响;2.通过基因芯片技术,分析在此过程中血管新生与神经新生相关基因表达的变化,探讨血管内皮细胞影响神经干细胞增殖分化的作用途径与机制,并采用real-time PCR方法对关键信号分子进行验证。
三.通过结扎3日龄新生SD大鼠双侧颈总动脉方法制备脑缺血模型后,随机分为治疗组(54只)和非治疗组(54只)。治疗组给予bFGF(10ng/g)侧脑室注射,非治疗组注射2μl生理盐水。另取54只3日龄新生SD大鼠作为假手术对照组(仅分离双侧颈总动脉,不结扎,不给予药物)。三组大鼠分别于术后第4d、7d、14d获取脑组织标本,采用免疫荧光双标、Western blot和real-time PCR的方法,观察三组大鼠不同时点SVZ巢蛋白(Nestin)、NeuN、胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)和少突胶质细胞NG2蛋白及其mRNA的表达变化,研究bFGF对神经干细胞新生和增殖分化的作用。
【结果】一.未成熟脑缺血性损伤后:1.脑组织病理切片可见SVZ神经细胞变性、坏死,细胞层次紊乱、排列松散,部分神经细胞固缩、胞浆深染、核浓缩,结构不清,以术后第4d损伤最重;2.免疫荧光标记结果显示SVZ新生细胞显著增加,包括神经干细胞(BrdU+/Nestin+)、神经元(BrdU+Tuj1+)、星形胶质细胞(BrdU+/GFAP+)和少突胶质细胞(BrdU+/O4+)数目均较对照组增加(P＜0.01),7d达高峰;3.基因芯片分析发现,与缺血后SVZ神经干细胞增殖分化相关的基因主要涉及VEGF、TGF-β1两条信号通路,定量分析结果显示VEGF、TGF-β1 mRNA和蛋白表达在缺血后均增加,7d达高峰,与对照组比较差异有统计学意义(p＜0.01)。
二.血管内皮细胞对未成熟脑神经干细胞的影响:1.共培养组神经干细胞(Nestin+)明显增加,在共培养7d达高峰,并且神经元(Tuj1+)、星形胶质细胞(GFAP+)和少突胶质细胞(O4+)数量亦增加,在共培养10d达高峰,与对照组和共培养+siRNA组相比,差异显著(P＜0.01)。2.与血管和神经新生相关的基因表达谱变化显示,共培养组有112个基因表达较对照组2倍以上升高,给予siRNA干预后,这112个上调的基因中有81个表达呈2倍以上降低。利用基因芯片显著性分析方法(significance analysis of microarray,SAM)筛选具有显著性表现的基因,并利用KEGG数据库将这些差异表达基因按照信号通路进行映射,发现显著性表现的基因主要涉及Notch和Pten信号通路,这两条信号通路与血管新生和神经干细胞增殖分化的调控有关。采用real-time PCR方法对这两条通路中主要基因进行验证,得到与芯片数据一致的结果。
三.未成熟脑缺血损伤后给予bFGF干预组:1.SVZ病理改变较对照组明显减轻;2.SVZ各种新生细胞(BrdU+)数量均较对照组显著增加,其中新生神经干细胞(BrdU+/Nestin+)在7d达高峰,而新生的神经元(BrdU+/NeuN+)、星形胶质细胞(BrdU+/GFAP+)和少突胶质细胞(BrdU+/NG2+)在14d达高峰,与非干预缺血组相比,差异均有显著意义(P＜0.01);3.Nestin蛋白和mRNA表达都在7d达高峰,NeuN、GFAP和NG2的蛋白和mRNA表达均在14d达高峰,与非干预缺血组相比,差异均有显著意义(P＜0.01)。
【结论】1.缺血促进未成熟脑SVZ神经干细胞的增殖及其向功能神经细胞的分化;2.VEGF和TGF-β信号通路参与调控缺血后神经干细胞的增殖分化,是缺血性损伤影响未成熟脑神经干细胞微环境的重要途径;3.血管内皮细胞分泌的可溶性细胞因子和对血管新生相关基因的抑制可影响神经干细胞的微环境,调节神经干细胞的增殖和分化;4.血管内皮细胞与神经干细胞的相互作用涉及多条通路,主要与Notch和Pten信号通路有关;5.bFGF干预可促进未成熟脑缺血后的神经新生,可能有助于缺血性损伤后的神经修复。
Objectives:Neural stem cell niche is a key factor to regulate the self-renewal, proliferation and differentiation of neural stem cells.However,little is known about how ischemia affects the neural stem cell niche in the premature brain.In order to clarify the mechanisms how ischemia effect on the neurogensis in the premature brain, we observed the proliferation and differentiation of neural stem cells and the changes of neural stem cell niche in a 3-day-old rat model following brain ischemia in this study.Furthermore,we elucidated the pathways which related to the neural stem cell niche through observing the effects of soluble factors secreted by vascular endothelial cells on proliferation and differentiation of neural stem cells.Besides,the effect of basic fibroblast growth factor(bFGF) on the proliferation and differentiation of neural stem cells after brain ischemia were investigated.The study will provide novel evidence for intervention of ischemic premature brain injury.
Methods:Part 1.The bilateral common carotid artery of rats was occluded to prepare the premature brain ischemia models.Proliferating cells were labeled by bromodeoxyuridine(BrdU) through intraperitoneal injection.By immunfluorescence staining,we observed the proliferation and differentiation of neural stem cells in the subventricular zone(SVZ) at 24h,4d,7d,and 14d after ischemic injury.And by used cDNA microarry chip,we monitored the changes of genes expression profile after brain ischemia.The significant change genes were testified by real-time quantitative polymerase chain reaction(PCR) and Western blot analysis.Part 2.SVZ brain slices of 3-day-old SD rats were cultured in vitro,they were divided into 3 groups randomly, named co-culture group(co-culture with vascular endothelial cells),co-culture and siRNA group(co-culture with vascular endothelial cells and siRNA) and control group(only culture brain slices),respectively.A mouse vascular endothelial cell line (bEnd.3,No.CRL-2299~(TM)) was used in the co-culture.RNA interference for knock-down VEGF gene expression was synthesized and transfection by liposome methods.At 4d,7d,and 10d of cultured,the proliferation and differentiation of neural stem cells in the brain slices were detected by immunfluorescence stain. Synchronously,the changes of genes involved neurogenesis and angiogenesis were analyzed by GeneChip and the relative signal pathways were further confirmed by real-time PCR.Part 3.One hundred and eight 3-day-old SD rats with brain ischemia were used in this experiment and half of them were received bFGF 10ng/g through lateral ventricles injection.Besides,fifty four 3-day-old SD rats without brain ischemia were used as normal control.Proliferating cells in brain were labeled by BrdU through intraperitoneal injection in a pulsed or a cumulative protocol.Rats were killed at 4d,7d,and 14d after operation,and the proliferation and differentiation of neural stem cells in the SVZ were observed by immunfluorescence assays,real-time PCR and Western blot analysis to evaluate the impact of bFGF on bain injury repair.
Results:Part 1:(1) There were cerebral edema widely;neuronal cells necrosis and focal cerebromalacia formation in the ischemic rats.These damages were the most serious at the 4th day after the operation.(2) In brain ischemic rats, BrdU+/Nestin+ cells in the SVZ were significantly increased at all four time points and more neural stem cells differentiated into neurons,astrocytes,and oligodendrocytes,compared with the rats without brain ischemia(P＜0.01).(3) GeneChip analysis showed a 3- to 10-fold increase in the mRNA expression of vascular endothelial growth factor(VEGF),transforming growth factor-beta (TGF-beta),and their receptors in the brain SVZ of ischemic rats,compared with that of without ischemic rats.PCR and Western blot analyses also confirmed these results. The data indicated that vascular endothelial growth factor and transforming growth factor-beta might be two important factors that involved post-ischemic neural stem cell proliferation and differentiation.Part 2:(1) The positive stain cells of Nestin, Tuj1,GFAP and O4 in brain slices were significantly increased in the co-culture group,compared with that in the control group(P＜0.01).But,when VEGF siRNA was added into the co-culture all these four type cells were decreased markedly (P＜0.01 vs the control group and co-culture group).(2) GeneChip analysis showed that the expressions of 112 genes were up-regulated more than 2-fold,however, among them 81 genes were down-regulated more than 2-fold after administration with VEGF siRNA.(3) Analyzed by "significance analysis of microarray" software,we found these noticeable altered genes were classified into notch and pten signal pathways on the ground of KEGG database,and these changes were further confirmed by real-time PCR assayes.Part 3:(1) The brain pathological damages in ischemic rats described in part 1 were alleviative in bFGF group.(2) Treatment with bFGF significantly increased the number of new cells(BrdU positive stain) in the SVZ at all three time points(P＜0.01).The new neural stem cells(BrdU/Nestin double positive cells) were peaked at 7d after operation,and amount in the bFGF group was more than that in the control group(P＜0.01).While,the new neurons(BrdU/NeuN double positive cells),astrocytes(BrdU/GFAP double positive cells),and oligodendrocytes(BrdU/NG2 double positive cells) were peaked at 14d.Treatment with bFGF significantly enhanced the number of these three group cells at all three time points(P＜0.01).Moreover,Real-time PCR and Western blot assay confirmed these results.
Conclusion:1.Ischemia induced the proliferation and differentiation of neural stem cells in the SVZ,which involved vascular endothelial growth factor and transforming growth factor-beta pathways.2.The soluble factors secreted by vascular endothelial cells enhance the proliferation and differentiation of neural stem cells in the SVZ.Moreover,inhibition of the expression of genes for angiogenesis attenuated the efficacy of vascular endothelial cells on neural stem cells.The effects of vascular endothelial cells on the neurogenesis were involved into many pathways,among them notch and pten signal pathways were important.3.bFGF stimulated the proliferation and differentiation of neural stem cells in neonatal rats after ischemic brain injury, which maybe is helpful for the neural repair after ischemia.
引文
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