中枢神经系统损伤后细胞增殖效应的实验研究
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摘要
成年动物中枢神经系统(Central Nervous Systerm,CNS)损伤后形成的胶质瘢痕是CNS再生失败的重要因素。既往的观点认为,成熟的胶质瘢痕是由细胞外成分(如IV型胶原和层粘连蛋白)和细胞成分(星形胶质细胞、成纤维细胞、巨噬细胞)等共同构成,其中反应性增生的星形胶质细胞是主要细胞成分。少突胶质前体细胞(oligodendrocyte precursor cell,OPC)是最近发现的CNS中除神经元、星形胶质细胞、少突胶质细胞、小胶质细胞之外的第五类细胞[1]。然而目前关于OPC是否参于CNS对损伤的反应及其意义方面的研究还较少。20世纪90年代初提出成年哺乳动物CNS存在神经干细胞(Neural Stem Cell, NSC)[2],并且大量的研究证实,NSC存在于CNS的广泛区域,这些NSC在体内大多处于静止状态,在CNS损伤等病理条件或外界信号分子的刺激下可以被激活并增殖。侧脑室壁的脑室下层(subventricular zone,SVZ)和海马齿状回的颗粒下层(subgranular zone,SGZ),是成体哺乳动物CNS中两个NSC富集区域。Parent等的研究证明多种脑损伤模型,可引起损伤远隔部位海马齿状回和室下区NSC的增殖,并且增殖的细胞可以分化为星形胶质细胞和神经元等[3]’[4]’[5]’[6]。故CNS损伤不仅可引起损伤部位胶质细胞的活化,还可以导致损伤部位及远隔部位NSCs的增殖。近年越来越多的研究显示,成年哺乳动物NSC只有在特定信号分子存在的微环境中才能分化为神经元[7]。有研究显示,BMP4与Noggin是一对对NSC的增殖分化有重要调控作用的蛋白分子。Lim等证实BMP4与Noggin共同调控成年室下区神经干细胞的分化,BMPs信号通过促进室下区NSC向星形胶质细胞分化,而抑制神经元的产生[8]。我们的研究发现在成年动物海马部位BMP4亦具有促进NSC向星形胶质细胞方向分化的功能[9]。然而BMP4与Noggin在除海马和室下区以外的其他部位是否具有类似的作用,BMP4与Noggin对CNS损伤后增殖细胞的分化有何作用,还有待进一步的研究证实。
本研究采用大鼠单侧眼球摘除作为动物模型,观察损伤后不同时间点对侧上丘GFAP、NG2阳性细胞的表达变化,证实单侧眼球摘除后确实存在脑内其投射部位对侧上丘的损伤并阐明GFAP阳性的星形胶质细胞、NG2阳性的OPC增殖的意义。第二部分采用BrdU标记的方法,观察单侧眼球摘除后损伤部位、海马齿状回和室下区BrdU阳性细胞的增殖,结合BrdU/GFAP、BrdU/DCX免疫荧光双标,探讨增殖阳性细胞的分化方向。最后一部分为进一步探讨影响CNS损伤后损伤部位增殖细胞分化的因素,采用原位杂交和Western-blot检测损伤后不同时间点对侧上丘BMP4 mRNA与Noggin mRNA的表达变化及Noggin蛋白的表达变化。
主要结果:
1.单侧眼球摘除后24h对侧上丘GFAP染色较正常对照组增加,术后24h时到1w这种表现进行性增加,至1w时上丘的GFAP阳性细胞数量达到顶峰,染色加深,突起增多增长。但术后1w到3w之间,GFAP染色并不进一步增加。
2.单侧眼球摘除后24h对侧上丘NG2染色加深,损伤后1w NG2阳性细胞数量达高峰,1w至3w之间NG2阳性细胞数量缓慢减少。
3.采用BrdU标记的方法,我们发现单侧眼球摘除后24h视神经的投射部位对侧上丘除血管内皮细胞外出现少量BrdU阳性细胞,1w时阳性细胞数量达高峰;损伤后2w时阳性细胞数量较1w时减少,3w时BrdU阳性细胞进一步减少。
4.单侧眼球摘除后24h双侧海马齿状回和室下区BrdU阳性细胞数量与对照组相比轻度升高,1w时BrdU阳性细胞数量达到高峰,2w至3w之间BrdU阳性细胞数量逐渐减少。除此之外我们还观察到,损伤后2w时,侧脑室背外侧角内阳性细胞数量增加,向外延伸的距离也明显增加;胼胝体内BrdU阳性细胞数量增多。
5.单侧眼球摘除后1w双侧海马齿状回和室下区DCX阳性细胞与对照组比较明显增多,随后的两周阳性细胞数量减少,3w时降至正常对照组水平。
6.免疫荧光双标显示:对侧上丘增殖的BrdU阳性细胞中可检测到少量BrdU/GFAP双标阳性细胞,无BrdU/DCX双标阳性细胞。海马齿状回和室下区增殖的BrdU阳性细胞存在BrdU/GFAP阳双标性细胞和BrdU/DCX双标阳性细胞。
7.BMP4 mRNA原位杂交实验发现,单侧眼球摘除后24h对侧上丘BMP4 mRNA阳性细胞数量较正常对照组明显增升高,染色加深,1w组BMP4mRNA的表达与24h组相比已开始降低,2w﹑3w组BMP4mRNA阳性细胞数量进一步减少,3w时降至正常水平。
8.各组对侧上丘Noggin mRNA的表达无明显差异,1w、2w﹑3w组与正常对照组相比均无明显变化,Western-blot实验结果也发现,Noggin蛋白的表达在各组无明显差异。
主要结论:
1.我们观察到单侧眼球摘除后对侧上丘GFAP阳性的星形胶质细胞反应性增生、NG2阳性的OPC活化,证实单侧眼球摘除后对侧上丘确实存在损伤反应,建立了一个新的、简便可行的CNS损伤的动物模型;同时证实除星形胶质细胞反应性增生外,CNS对损伤的反应还包括NG2阳性的OPC活化。
2.CNS损伤不仅可以引起损伤局部包括星形胶质细胞和OPC在内的胶质细胞反应,还可以诱导损伤局部出现BrdU阳性细胞,海马齿状回和室下区BrdU阳性细胞数量增加,这些部位增殖的BrdU阳性细胞中存在星形胶质细胞和神经元前体细胞。
3.CNS损伤后BMP4与Noggin的表达可能是调控损伤后损伤部位增殖细胞分化的重要因素。
Glia scar formed in adult central nervous system(CNS) injury has been considered as the major facor of the faliure of regeneration.Traditionally, mature glia scar include some extral celluar ingredients(such as type-IV collagan, laminin) and celluar ingredients(such as astrocytes, fibroblasts, macrophages).Reactive astrocytes are the major components of glia scar. Oligodendrocyte precursor cells ,briefly OPCs, are the fifth element in the CNS, in addition to neurons, astrocytes, oligodendrocytes and microglia, which has been recently detected[1]. However,there has not been much research on the reaction of OPCs in CNS injury.In 1990s neural stem cells(NSC) has been confirmed to exsit in various regions of CNS[2] .Those stem cells are mostly dormant ,but they react to CNS injury and other exogenous signals by activating and proliferating. Subventricular zone(SVZ) of the lateral ventricle and subgranular zone(SGZ) of the dentate gyrus are the two neurogenic regions of the adult mamalian central nervous system. Parent’s researches confirmed that many experimental brain injury can arouse the proliferation of NSC in distant SVZ and SGZ, and these cells has the ability to develop into astrocyes as well as neurons[3],[4],[5],[6].So,adult CNS react to injury not only by reactive gliosis,but by the proliferation of distant NSCs.Recently more and more researches indicate that ,adult mamalian NSC can differentiate into neurons in special niches [7].BMP4 and Noggin has important roles in modulate the proliferation and differentiation of NSCs.Lim et. al found that BMP4 and Noggin cooperate to affect the differentiation of the stem cells in SVZ,BMPs promote the generation of astrocytes ,concurrently inhibit neurogenesis[8]. Reasearches into adult hippocampaus also find that BMP4 has the ability of promoting the generation of astrocytes[9].Whether BMP4 and Noggin has the same function in regions other than SVZ and SGZ and How it affect the differentiation of the proliferating cells after CNS injury,needs further study.
This research use unilateral eye ball enucleation as the CNS injury model. And then detectting the change of GFAP, NG2 IR cells in contralateral superior colliculus at different time points to confirm that after unilateral eye ball enucleation there has been injury reactions in contralateral superior colliculus in the brain . In addition we try to investigate the significance of the proliferation of GFAP positive astrocytes and NG2 positive OPCs.In the second part, we use BrdU labelling method to detect the proliferation of BrdU positive cells in the injury place, dentate gyrus and subventricular zone. Combined with BrdU/GFAP, BrdU/DCX immunofluorescence double labelling ,we further investigate the differentiation of the proliferating cells.In the last part ,to investigate the factors affecting the differtiation of the proliferating cells in the injury place ,we use in situ hybridization and westen-blot to detect the expression of BMP4 mRNA ,Noggin mRNA and Noggin protein.
The main results are as follows:
1. 24 hours after unilateral eye ball enucleation the immunostaining of GFAP in contralateral superior colliculus increaded compared with control group, this staining progressively increased during 24h to 1 week and reached the top at the time point of 1 week. But in the time span of 1 week to 3 week there has been no increase.
2. 24 hours after unilateral eye ball enucleation the immunostaining of NG2 in contralateral superior colliculus increaded obviously. The number of the NG2 IR cells reached the top amount at 1 week, and then decrease slowly in the following two weeks.
3. Use BrdU labelling method,we find that 24h after unilateral eye ball enucleation some BrdU IR cells was detected in contralateral superior colliculus .There has been most BrdU IR cells at 1 week, and decrease obviously in 2 week group and 3 week group.
4. 24 hours after unilateral eye ball enucleation the number of BrdU IR cells in dentate gyrus and SVZ increased slightly,reached the top at 1 week ,and then gradually decreased in the following two weeks. Additionally we find that 2 weeks after the injury the number of BrdU IR cells in the dorsalateral SVZ has been obviously increased, and the distance it extends also increased. 2 weeks after the injury the number of BrdU IR cells in corpus callosum increased.
5. 1 week after unilateral eye ball enucleation the number of DCX IR cells in both dentate gyrus and SVZ increased obviously compared with control group, decreased in the following 2 weeks and then reach the control group level at 3 week.
6. Immunofluorescence double labelling indicate that, the BrdU IR cells in contralateral superior colliculus include some BrdU/GFAP double labelling cells, without BrdU/DCX double labelling cells. The BrdU IR cells in dentate gyrus and SVZ has both BrdU/GFAP and BrdU/DCX double labelling cells.
7. In situ hybridization indicate that , 24 hours after unilateral eye ball enucleation the number of BMP4 mRNA IR cells increased obviously compared with the control group, 1 week group decreased compared with 24 hour group, and decreased gradually in 2 week and 3 week groups.
8. However, the expression of Noggin mRNA in each group has no obvious change, the expression of Noggin protein indicated by western-blot also hasn’t any change in each group.
The main conclusions:
1. Both GFAP IR astrocytes and NG2 IR OPCs react to unilateral eye ball enucleation, which indicate that contralateral superior colliculus did undergo an injury after unilateral eye ball enucleation. We established a new, easy CNS injury animal model by enucleate the eye ball of the animal. At the same time we confirm that except reactive astrogliosis, OPCs are activated in CNS injury.
2. Besides reactive gliosis (including astrocytes and OPCs), CNS injury can also initiate the proliferating of BrdU IR cells in the injury place ,dendrate gyrus and SVZ.The proliferating cells in the injury place can only differertiate into astrocytes, while the proliferating cells in dendrate gyrus and SVZ can develop into both astrocytes and neuroprecursors.
3. The expression of BMP4 and Noggin may be important for the differentiating of the proliferating BrdU IR cells in the injury place.
本研究采用大鼠单侧眼球摘除作为动物模型,观察损伤后不同时间点对侧上丘GFAP、NG2阳性细胞的表达变化,证实单侧眼球摘除后确实存在脑内其投射部位对侧上丘的损伤并阐明GFAP阳性的星形胶质细胞、NG2阳性的OPC增殖的意义。第二部分采用BrdU标记的方法,观察单侧眼球摘除后损伤部位、海马齿状回和室下区BrdU阳性细胞的增殖,结合BrdU/GFAP、BrdU/DCX免疫荧光双标,探讨增殖阳性细胞的分化方向。最后一部分为进一步探讨影响CNS损伤后损伤部位增殖细胞分化的因素,采用原位杂交和Western-blot检测损伤后不同时间点对侧上丘BMP4 mRNA与Noggin mRNA的表达变化及Noggin蛋白的表达变化。
主要结果:
1.单侧眼球摘除后24h对侧上丘GFAP染色较正常对照组增加,术后24h时到1w这种表现进行性增加,至1w时上丘的GFAP阳性细胞数量达到顶峰,染色加深,突起增多增长。但术后1w到3w之间,GFAP染色并不进一步增加。
2.单侧眼球摘除后24h对侧上丘NG2染色加深,损伤后1w NG2阳性细胞数量达高峰,1w至3w之间NG2阳性细胞数量缓慢减少。
3.采用BrdU标记的方法,我们发现单侧眼球摘除后24h视神经的投射部位对侧上丘除血管内皮细胞外出现少量BrdU阳性细胞,1w时阳性细胞数量达高峰;损伤后2w时阳性细胞数量较1w时减少,3w时BrdU阳性细胞进一步减少。
4.单侧眼球摘除后24h双侧海马齿状回和室下区BrdU阳性细胞数量与对照组相比轻度升高,1w时BrdU阳性细胞数量达到高峰,2w至3w之间BrdU阳性细胞数量逐渐减少。除此之外我们还观察到,损伤后2w时,侧脑室背外侧角内阳性细胞数量增加,向外延伸的距离也明显增加;胼胝体内BrdU阳性细胞数量增多。
5.单侧眼球摘除后1w双侧海马齿状回和室下区DCX阳性细胞与对照组比较明显增多,随后的两周阳性细胞数量减少,3w时降至正常对照组水平。
6.免疫荧光双标显示:对侧上丘增殖的BrdU阳性细胞中可检测到少量BrdU/GFAP双标阳性细胞,无BrdU/DCX双标阳性细胞。海马齿状回和室下区增殖的BrdU阳性细胞存在BrdU/GFAP阳双标性细胞和BrdU/DCX双标阳性细胞。
7.BMP4 mRNA原位杂交实验发现,单侧眼球摘除后24h对侧上丘BMP4 mRNA阳性细胞数量较正常对照组明显增升高,染色加深,1w组BMP4mRNA的表达与24h组相比已开始降低,2w﹑3w组BMP4mRNA阳性细胞数量进一步减少,3w时降至正常水平。
8.各组对侧上丘Noggin mRNA的表达无明显差异,1w、2w﹑3w组与正常对照组相比均无明显变化,Western-blot实验结果也发现,Noggin蛋白的表达在各组无明显差异。
主要结论:
1.我们观察到单侧眼球摘除后对侧上丘GFAP阳性的星形胶质细胞反应性增生、NG2阳性的OPC活化,证实单侧眼球摘除后对侧上丘确实存在损伤反应,建立了一个新的、简便可行的CNS损伤的动物模型;同时证实除星形胶质细胞反应性增生外,CNS对损伤的反应还包括NG2阳性的OPC活化。
2.CNS损伤不仅可以引起损伤局部包括星形胶质细胞和OPC在内的胶质细胞反应,还可以诱导损伤局部出现BrdU阳性细胞,海马齿状回和室下区BrdU阳性细胞数量增加,这些部位增殖的BrdU阳性细胞中存在星形胶质细胞和神经元前体细胞。
3.CNS损伤后BMP4与Noggin的表达可能是调控损伤后损伤部位增殖细胞分化的重要因素。
Glia scar formed in adult central nervous system(CNS) injury has been considered as the major facor of the faliure of regeneration.Traditionally, mature glia scar include some extral celluar ingredients(such as type-IV collagan, laminin) and celluar ingredients(such as astrocytes, fibroblasts, macrophages).Reactive astrocytes are the major components of glia scar. Oligodendrocyte precursor cells ,briefly OPCs, are the fifth element in the CNS, in addition to neurons, astrocytes, oligodendrocytes and microglia, which has been recently detected[1]. However,there has not been much research on the reaction of OPCs in CNS injury.In 1990s neural stem cells(NSC) has been confirmed to exsit in various regions of CNS[2] .Those stem cells are mostly dormant ,but they react to CNS injury and other exogenous signals by activating and proliferating. Subventricular zone(SVZ) of the lateral ventricle and subgranular zone(SGZ) of the dentate gyrus are the two neurogenic regions of the adult mamalian central nervous system. Parent’s researches confirmed that many experimental brain injury can arouse the proliferation of NSC in distant SVZ and SGZ, and these cells has the ability to develop into astrocyes as well as neurons[3],[4],[5],[6].So,adult CNS react to injury not only by reactive gliosis,but by the proliferation of distant NSCs.Recently more and more researches indicate that ,adult mamalian NSC can differentiate into neurons in special niches [7].BMP4 and Noggin has important roles in modulate the proliferation and differentiation of NSCs.Lim et. al found that BMP4 and Noggin cooperate to affect the differentiation of the stem cells in SVZ,BMPs promote the generation of astrocytes ,concurrently inhibit neurogenesis[8]. Reasearches into adult hippocampaus also find that BMP4 has the ability of promoting the generation of astrocytes[9].Whether BMP4 and Noggin has the same function in regions other than SVZ and SGZ and How it affect the differentiation of the proliferating cells after CNS injury,needs further study.
This research use unilateral eye ball enucleation as the CNS injury model. And then detectting the change of GFAP, NG2 IR cells in contralateral superior colliculus at different time points to confirm that after unilateral eye ball enucleation there has been injury reactions in contralateral superior colliculus in the brain . In addition we try to investigate the significance of the proliferation of GFAP positive astrocytes and NG2 positive OPCs.In the second part, we use BrdU labelling method to detect the proliferation of BrdU positive cells in the injury place, dentate gyrus and subventricular zone. Combined with BrdU/GFAP, BrdU/DCX immunofluorescence double labelling ,we further investigate the differentiation of the proliferating cells.In the last part ,to investigate the factors affecting the differtiation of the proliferating cells in the injury place ,we use in situ hybridization and westen-blot to detect the expression of BMP4 mRNA ,Noggin mRNA and Noggin protein.
The main results are as follows:
1. 24 hours after unilateral eye ball enucleation the immunostaining of GFAP in contralateral superior colliculus increaded compared with control group, this staining progressively increased during 24h to 1 week and reached the top at the time point of 1 week. But in the time span of 1 week to 3 week there has been no increase.
2. 24 hours after unilateral eye ball enucleation the immunostaining of NG2 in contralateral superior colliculus increaded obviously. The number of the NG2 IR cells reached the top amount at 1 week, and then decrease slowly in the following two weeks.
3. Use BrdU labelling method,we find that 24h after unilateral eye ball enucleation some BrdU IR cells was detected in contralateral superior colliculus .There has been most BrdU IR cells at 1 week, and decrease obviously in 2 week group and 3 week group.
4. 24 hours after unilateral eye ball enucleation the number of BrdU IR cells in dentate gyrus and SVZ increased slightly,reached the top at 1 week ,and then gradually decreased in the following two weeks. Additionally we find that 2 weeks after the injury the number of BrdU IR cells in the dorsalateral SVZ has been obviously increased, and the distance it extends also increased. 2 weeks after the injury the number of BrdU IR cells in corpus callosum increased.
5. 1 week after unilateral eye ball enucleation the number of DCX IR cells in both dentate gyrus and SVZ increased obviously compared with control group, decreased in the following 2 weeks and then reach the control group level at 3 week.
6. Immunofluorescence double labelling indicate that, the BrdU IR cells in contralateral superior colliculus include some BrdU/GFAP double labelling cells, without BrdU/DCX double labelling cells. The BrdU IR cells in dentate gyrus and SVZ has both BrdU/GFAP and BrdU/DCX double labelling cells.
7. In situ hybridization indicate that , 24 hours after unilateral eye ball enucleation the number of BMP4 mRNA IR cells increased obviously compared with the control group, 1 week group decreased compared with 24 hour group, and decreased gradually in 2 week and 3 week groups.
8. However, the expression of Noggin mRNA in each group has no obvious change, the expression of Noggin protein indicated by western-blot also hasn’t any change in each group.
The main conclusions:
1. Both GFAP IR astrocytes and NG2 IR OPCs react to unilateral eye ball enucleation, which indicate that contralateral superior colliculus did undergo an injury after unilateral eye ball enucleation. We established a new, easy CNS injury animal model by enucleate the eye ball of the animal. At the same time we confirm that except reactive astrogliosis, OPCs are activated in CNS injury.
2. Besides reactive gliosis (including astrocytes and OPCs), CNS injury can also initiate the proliferating of BrdU IR cells in the injury place ,dendrate gyrus and SVZ.The proliferating cells in the injury place can only differertiate into astrocytes, while the proliferating cells in dendrate gyrus and SVZ can develop into both astrocytes and neuroprecursors.
3. The expression of BMP4 and Noggin may be important for the differentiating of the proliferating BrdU IR cells in the injury place.
引文
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[2] Reynolds, B.A., and Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system.Science, 1992,255:1707–1710
[3] Parent JM, Vexler ZS , Gong C , et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol, 2002 , 52 (6) : 802 - 813.
[4] Parent JM, Valentin VV, Lowenstein DH. Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. J Neurosci 2002, 22(8):3174-88.
[5] Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH.Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 1997, 17(10):3727-38.
[6] Parent JM.Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist 2003, 9 (4) :261-72
[7] Alvarez-Buylla A, Lim DA. For the Long Run:Maintaining Germinal Niches in the Adult Brain.Neuron, 2004, 41(5): 683～686.
[8] Lim DA, Tramontin AD, Trevejo JM, et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron,2000,28:713～726.
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