胚胎神经干细胞对于死后人脑老化神经元的促存活作用研究
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摘要
由于干细胞具有自我增殖,分化和修复的特性,外源性神经干细胞移植治疗神经系统退行性疾病成为人们关注的热点,虽然在帕金森氏病的治疗方面显示出一定的临床应用前景。但是细胞移植的定点性决定了其治疗的区域性的特点,对于病变累及广泛的神经退行性疾病,比如阿尔茨海默病(Alzheimer disease,AD)并不是一个完美的治疗方案。理想的方案应当是神经干细胞所释放的物质可广泛的作用于AD不同区域的脑组织。在AD的病理改变中给我们留的一个机会是:AD脑内大量神经元并没有死亡而是“失活”,适当的刺激可使失活的神经元再激活。我们的假设是:AD脑组织中广泛受累“失活”的神经元或者“沉默”的神经元可被外源性神经干细胞来源的因子修复或再激活,从而恢复神经元的部分功能。
为验证该假设,本实验将死后人脑组织运动皮层脑组织切片(AD组,n=7;老年非痴呆对照组,n=6)与大鼠胚胎来源的神经干细胞体外“分离式”共培养,对AD脑组织进行细胞活性检查(live/dead kit),结果发现:
1.体外培养的死后脑组织仍具有活性。
Live/dead kit染色显示培养的AD脑组织存在活细胞(绿色胞浆,空细胞核),死细胞(红色细胞核),中间态细胞(绿色胞浆,红色细胞核)。在体外组织培养(0-30天)的过程中,三种细胞数目没有随着培养时间的延长发生显著性改变,p值分别为0.91,0.09,0.78。
2.在正常培养的条件下AD脑片包含更少的活的神经元。
AD来源的脑片的存活神经元数目少于正常对照组(P=0.017),并且显示出较老年对照明显的个体差异。
3.干细胞共培养可促进死后脑组织的存活状态。
与未处理组或成纤维细胞共培养组(作为干细胞的对照)相比,神经干细胞共培养组的脑片有更多的存活细胞(约增加2600个/mm~2,p＜0.001)和更少的死细胞(约减少9500个/mm~2,p＜0.001)。而共培养没有明显增加两组脑片中间态的细胞数目(p=0.36)。
上述结果证明了共培养具有神经保护和促进损伤修复的作用,接下来的问题是:存活的细胞是否具有转录活性?本研究进一步探讨了神经干细胞共培养对人脑组织转录水平的影响,运用荧光实时定量PCR的方法,检测了在共培养期间常规参考基因及神经元特异性烯醇化酶(NSE),应激相关基因JIP-1的mRNA水平的改变。
1.没有表达恒定的“参考基因”。
在死后脑组织培养体系中,没有检测到表达水平恒定的“参考基因”(GAPGH,EF1α,β-actin,YWHAZ,UBC),但是上述基因表达显示出很高的相关性。
2.神经干细胞诱导老化神经元产生更多的NSE mRNA。
NSE是神经元特异性表达的基因,参与神经元的糖酵解过程。在老年对照组,神经干细胞共培养组的脑片显示出较高NSE的转录水平,采用在内部平衡的2-△CT'[△Ct'=Ct(DIV10)-Ct(未处理DIV3)]法分析PCR结果显示P＜0.001(ANOVA)或者p=0.021(Mann-Whitney),提示共培养处理组神经元的转录水平显著高于未处理组。同细胞活性染色一致,AD组的NSE mRNA水平亦较对照组为低。
3.体外培养的AD脑片未检测到应激敏感蛋白JIP-1的表达。
JIP-1是参与JNK和AKT信号转导途径的应激敏感型蛋白,最新研究发现与磷酸化的β淀粉样蛋白前体的运输有关。在冻存老年和AD脑组织均检测到稳定的JIP-1mRNA表达,但是培养的AD脑片中未检测到其mRNA存在提示AD神经元对外界的反应较对照组低下。
4.慢病毒载体转染的神经干细胞神经元分化率低,没有成功建立体转染和外移植模型。
综上所述,本实验采用人脑组织,结合独特的“隔离式”共培养的体系,避免了移植实验中的细胞转化所造成的效应,首次报道了神经干细胞对于人脑衰老或退行性变神经元的细胞具有促进存活和提高转录活动的作用。虽然其作用机制仍需要进一步阐明,但本研究提供的人脑组织基础上的实验资料为临床神经退行性疾病的治疗提出了一条新思路。
Neurodegenerative diseases are progressive and incurable and are becoming ever more prevalent. To study whether neural stem cells can reactivate or rescue functions of impaired neurons in the human aging and neurodegenerating brain, we co-cultured postmortem slices from Alzheimer patients and control subjects with rat embryonic day 14 (E14) neural stem cells. Human Postmortem brain slices from the elderly control and Alzheimer's disease (AD) (n=13) were co-cultured with NSC without direct contact or by cell fusion using separated co-culturing system. Immunohistochemistry and viability staining were used to evaluate the morphological features and survival of the human neurons in neocortical tissue on different days in vitro ranged from 0 to 38.
Viability staining, based on the exclusion of ethidium bromide by intact plasma membranes, showed that there were strikingly more viable cells and fewer dead cells in co-cultured slices than in untreated slices. The presence of Alzheimer pathology in the brain slices did not influence this effect, although the slices from Alzheimer patients, in general, contained fewer viable cells. Co-culturing with rat E14 fibroblasts did not improve the viability of neurons in the human brain slices. Since the human slices and neural stem cells were separated by a membrane during co-culturing our data show for the first time that neural stem cells release diffusible factors that may improve the survival of aged and degenerating neurons in human brains.
Data analysis revealed that there was no significant changes over time viable (p=0.41), leaky (p=0.72) and dead (p=0.70) by patient. Visual inspection of untreated slices stained with the Live/Dead kit did not show any obvious differences between tissue from control subjects and AD patients. However, cell counts revealed that the number of viable cells in untreated slices of AD patients was reduced by 55 % as compared with untreated slices from control subjects and the reduction was significant (P = 0.02), whereas the differences in leaky, dead and total cell number were not significant. Taking controls and Alzheimer patients together, the effect of treatment with neural stem cells consisted of an average increase of 2600 viable cells per mm~3 (P < 0.001). The number of leaky cells roughly remained the same (P = 0.36), while the mean number of dead cells and the mean total number of cells decreased with about 9500 (P < 0.001) and 7800 (P = 0.009) per mm~3, respectively. The high variability of the viability in co-cultured slices from AD patients, however, suggests that tissue from some AD patients responded less well to treatment with neural stem cells.
To further confirm the neuronal survival in our culture system, Total RNA was isolated from cultured slices of 8 brains (AD n=4, aging control n=4) and real time PCR was performed using SYBR greenI dye to explore the expression of neuronal related genes on transcriptional level, including neuronal enclose 2 (NSE) and JNK-interacting protein1 (JIP1). Our data showed even the input RNA amount was equal at the start of cDNA synthesis, none of so called "reference genes" expressed constantly during culture. In the following study, we, therefore used the method of 2~(△CT) to normalize the target gene externally and determine whether the mRNA amount could be affected by the treatment.
△Ct'=Ct_((DIV10))- Ct_((untreated DIV3))
NSE gene is found in mature neurons and cells of neuronal origin. In 4 elderly non-dementia control, mock-treated slices from different elderly control subjects showed similar level of delta Ct', which indicates a relative stable survival system of human postmortem brain slices regardless the day in vitro. Co-cultured human brain slices contained an obvious higher amount of NSE mRNA after 10 days in co-culture than mock-treated slices (p=0.021 by Mann- Whitney), indicating a significant increase of NSE mRNA induced by NSC.
Untreated brain slices from AD patients showed too low transcription level of NSE, only 1 AD patient showed reliable NSE template amount (Ct<32) and again, co-cultured slices from this AD patient displayed higher transcription level of NSE after 10 days co-culture. To examine the responsive capacity of AD brains, we further investigated the changes of JIP1, which could be regulated by the environmental stress, as a marker of neuron responsible ability to the environment stress in vitro. JIP1 mRNA was easily detectable in frozen tissue from 1 AD brain (Ct=28.90) and 2 elderly control brains (Ct=28.77 and 29.79). However, under culture conditions, no or only a doubtful amount of mRNA of JIP-1 was detected in all four cultured AD slices, whereas it was detected in larger amounts in all elderly controls subjects (Ct=31.9, 32.7,29.8, 27.8). Electrophoresis of the PCR products showed that even the elderly control patient with a very low total RNA amount (C4) displayed a different pattern of JIP expression as compared with AD (AD5).
Our data indicate that human aged brain tissue could make communications with NSC even without direct contact. These findings may have potential for the clinical use of NSC in aging related diseases.
为验证该假设,本实验将死后人脑组织运动皮层脑组织切片(AD组,n=7;老年非痴呆对照组,n=6)与大鼠胚胎来源的神经干细胞体外“分离式”共培养,对AD脑组织进行细胞活性检查(live/dead kit),结果发现:
1.体外培养的死后脑组织仍具有活性。
Live/dead kit染色显示培养的AD脑组织存在活细胞(绿色胞浆,空细胞核),死细胞(红色细胞核),中间态细胞(绿色胞浆,红色细胞核)。在体外组织培养(0-30天)的过程中,三种细胞数目没有随着培养时间的延长发生显著性改变,p值分别为0.91,0.09,0.78。
2.在正常培养的条件下AD脑片包含更少的活的神经元。
AD来源的脑片的存活神经元数目少于正常对照组(P=0.017),并且显示出较老年对照明显的个体差异。
3.干细胞共培养可促进死后脑组织的存活状态。
与未处理组或成纤维细胞共培养组(作为干细胞的对照)相比,神经干细胞共培养组的脑片有更多的存活细胞(约增加2600个/mm~2,p＜0.001)和更少的死细胞(约减少9500个/mm~2,p＜0.001)。而共培养没有明显增加两组脑片中间态的细胞数目(p=0.36)。
上述结果证明了共培养具有神经保护和促进损伤修复的作用,接下来的问题是:存活的细胞是否具有转录活性?本研究进一步探讨了神经干细胞共培养对人脑组织转录水平的影响,运用荧光实时定量PCR的方法,检测了在共培养期间常规参考基因及神经元特异性烯醇化酶(NSE),应激相关基因JIP-1的mRNA水平的改变。
1.没有表达恒定的“参考基因”。
在死后脑组织培养体系中,没有检测到表达水平恒定的“参考基因”(GAPGH,EF1α,β-actin,YWHAZ,UBC),但是上述基因表达显示出很高的相关性。
2.神经干细胞诱导老化神经元产生更多的NSE mRNA。
NSE是神经元特异性表达的基因,参与神经元的糖酵解过程。在老年对照组,神经干细胞共培养组的脑片显示出较高NSE的转录水平,采用在内部平衡的2-△CT'[△Ct'=Ct(DIV10)-Ct(未处理DIV3)]法分析PCR结果显示P＜0.001(ANOVA)或者p=0.021(Mann-Whitney),提示共培养处理组神经元的转录水平显著高于未处理组。同细胞活性染色一致,AD组的NSE mRNA水平亦较对照组为低。
3.体外培养的AD脑片未检测到应激敏感蛋白JIP-1的表达。
JIP-1是参与JNK和AKT信号转导途径的应激敏感型蛋白,最新研究发现与磷酸化的β淀粉样蛋白前体的运输有关。在冻存老年和AD脑组织均检测到稳定的JIP-1mRNA表达,但是培养的AD脑片中未检测到其mRNA存在提示AD神经元对外界的反应较对照组低下。
4.慢病毒载体转染的神经干细胞神经元分化率低,没有成功建立体转染和外移植模型。
综上所述,本实验采用人脑组织,结合独特的“隔离式”共培养的体系,避免了移植实验中的细胞转化所造成的效应,首次报道了神经干细胞对于人脑衰老或退行性变神经元的细胞具有促进存活和提高转录活动的作用。虽然其作用机制仍需要进一步阐明,但本研究提供的人脑组织基础上的实验资料为临床神经退行性疾病的治疗提出了一条新思路。
Neurodegenerative diseases are progressive and incurable and are becoming ever more prevalent. To study whether neural stem cells can reactivate or rescue functions of impaired neurons in the human aging and neurodegenerating brain, we co-cultured postmortem slices from Alzheimer patients and control subjects with rat embryonic day 14 (E14) neural stem cells. Human Postmortem brain slices from the elderly control and Alzheimer's disease (AD) (n=13) were co-cultured with NSC without direct contact or by cell fusion using separated co-culturing system. Immunohistochemistry and viability staining were used to evaluate the morphological features and survival of the human neurons in neocortical tissue on different days in vitro ranged from 0 to 38.
Viability staining, based on the exclusion of ethidium bromide by intact plasma membranes, showed that there were strikingly more viable cells and fewer dead cells in co-cultured slices than in untreated slices. The presence of Alzheimer pathology in the brain slices did not influence this effect, although the slices from Alzheimer patients, in general, contained fewer viable cells. Co-culturing with rat E14 fibroblasts did not improve the viability of neurons in the human brain slices. Since the human slices and neural stem cells were separated by a membrane during co-culturing our data show for the first time that neural stem cells release diffusible factors that may improve the survival of aged and degenerating neurons in human brains.
Data analysis revealed that there was no significant changes over time viable (p=0.41), leaky (p=0.72) and dead (p=0.70) by patient. Visual inspection of untreated slices stained with the Live/Dead kit did not show any obvious differences between tissue from control subjects and AD patients. However, cell counts revealed that the number of viable cells in untreated slices of AD patients was reduced by 55 % as compared with untreated slices from control subjects and the reduction was significant (P = 0.02), whereas the differences in leaky, dead and total cell number were not significant. Taking controls and Alzheimer patients together, the effect of treatment with neural stem cells consisted of an average increase of 2600 viable cells per mm~3 (P < 0.001). The number of leaky cells roughly remained the same (P = 0.36), while the mean number of dead cells and the mean total number of cells decreased with about 9500 (P < 0.001) and 7800 (P = 0.009) per mm~3, respectively. The high variability of the viability in co-cultured slices from AD patients, however, suggests that tissue from some AD patients responded less well to treatment with neural stem cells.
To further confirm the neuronal survival in our culture system, Total RNA was isolated from cultured slices of 8 brains (AD n=4, aging control n=4) and real time PCR was performed using SYBR greenI dye to explore the expression of neuronal related genes on transcriptional level, including neuronal enclose 2 (NSE) and JNK-interacting protein1 (JIP1). Our data showed even the input RNA amount was equal at the start of cDNA synthesis, none of so called "reference genes" expressed constantly during culture. In the following study, we, therefore used the method of 2~(△CT) to normalize the target gene externally and determine whether the mRNA amount could be affected by the treatment.
△Ct'=Ct_((DIV10))- Ct_((untreated DIV3))
NSE gene is found in mature neurons and cells of neuronal origin. In 4 elderly non-dementia control, mock-treated slices from different elderly control subjects showed similar level of delta Ct', which indicates a relative stable survival system of human postmortem brain slices regardless the day in vitro. Co-cultured human brain slices contained an obvious higher amount of NSE mRNA after 10 days in co-culture than mock-treated slices (p=0.021 by Mann- Whitney), indicating a significant increase of NSE mRNA induced by NSC.
Untreated brain slices from AD patients showed too low transcription level of NSE, only 1 AD patient showed reliable NSE template amount (Ct<32) and again, co-cultured slices from this AD patient displayed higher transcription level of NSE after 10 days co-culture. To examine the responsive capacity of AD brains, we further investigated the changes of JIP1, which could be regulated by the environmental stress, as a marker of neuron responsible ability to the environment stress in vitro. JIP1 mRNA was easily detectable in frozen tissue from 1 AD brain (Ct=28.90) and 2 elderly control brains (Ct=28.77 and 29.79). However, under culture conditions, no or only a doubtful amount of mRNA of JIP-1 was detected in all four cultured AD slices, whereas it was detected in larger amounts in all elderly controls subjects (Ct=31.9, 32.7,29.8, 27.8). Electrophoresis of the PCR products showed that even the elderly control patient with a very low total RNA amount (C4) displayed a different pattern of JIP expression as compared with AD (AD5).
Our data indicate that human aged brain tissue could make communications with NSC even without direct contact. These findings may have potential for the clinical use of NSC in aging related diseases.
引文
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