摘要
少突胶质细胞前体细胞(oligodendrocyte precursor cells,OPCs)是成年中枢神经系统中广泛分布的干细胞或干细胞样细胞,体外培养成年OPCs具有自我更新增殖和不对称分化能力,其标记物有NG2、血小板衍化生长因子α受体(platelet derived growth factors receptorα, PDGFR-α)和O4。OPCs与病毒感染、免疫反应、神经退行性疾病、CO等毒性物质作用及营养代谢障碍和缺血缺氧所致的白质损害密切相关。但对OPCs在中枢神经系统发育分化及再生中的作用,尚存在众多有待解决的问题。OPCs是少突胶质细胞的细胞系,但是否仅是少突胶质细胞的后备储存池尚存在众多的质疑。NG2+细胞的分布,在灰质多于髓鞘生成区-白质,在缺氧、缺血、外伤、炎症及毒性物质作用下产生明显的反应性增殖,它区别于星形胶质细胞和小胶质细胞在于其反应为一过性的、而且局限于伤灶周围。在神经退行性疾病如侧束硬化症时NG2+细胞数量增多而且免疫反应显著加强。但至今为止,在整体实验中,OPCs移植有报告能改善髓鞘生成,但未能提供OPC参加损伤修复、增强髓鞘生成的直接实验依据。有关OPCs的细胞生物学及电生理特性特别是发育分化方面的研究,国内少有报告。
脑缺血缺氧损伤已成为新生儿脑损伤的重要形式,婴幼儿发育中脑对缺血缺氧的易感性,常导致脑室周围白质软化(periventricular leukomalacia, PVL),临床称为小儿脑瘫。尽管当今围产期监测、孕期和新生儿监护等方面的医疗技术取得了长足的发展,但是新生儿缺血缺氧性脑病(hypoxic-ischemic encephalopathy, HIE)的发生率却无明显降低,平均每1000和活产足月儿中,就有3-4个婴儿发病,早产儿的发病率更高,其中10%-60%在新生儿期失望,25%以上的患儿遗留永久的神经心理缺陷,如脑瘫、精神发育迟滞、学习困难和癫痫。少突胶质前体细胞损伤是PWMI形成的主要原因和中心环节。未成熟脑白质中对缺氧缺血高度敏感的OPCs的大量死亡以及分化发育障碍是PWMI形成的关键。因此,深入研究OPCs缺氧缺血性损伤机制,是阐明早产儿脑白质损伤机理,寻找预防和治疗药物,降低早产儿死亡率和致残率的重要途径。迄今为止,对OPCs缺氧缺血损伤机制所知有限,可能与谷氨酸兴奋毒性、炎症介质、氧化应激、细胞内Ca2+超载等多种因素有关。然而针对这些机制的干预措施并未转化为临床治疗成果。
肾母细胞瘤过度表达基因(Nephroblastoma Overexpression gene, NOV)是一种原癌基因。其所编码产物(NOV蛋白)是一种胰岛素样生长因子(Insulin-like Growth Factor,IGF)结合蛋白(IGF-binding proteins, IGFBPs),属于IGF家族的成员,它通过调节IGF与IGF受体的结合状态而对IGF功能的发挥调控作用,具有影响神经干细胞增殖、分化和存活的功能。IGF-I是属于胰岛素家族成员,是一类多功能多效应的细胞增殖调控因子。目前研究认为IGF-I是神经干细胞增殖所必需,IGF-1可依循受体酪氨酸蛋白激酶途径作用与神经干细胞。缺乏IGF-I的作用,bFGF和EGF都不能有效刺激体外神经干细胞的增殖,同时IGF-I可以促进神经干细胞分化成少突胶质细胞。OPCs属于具干细胞性质的前体细胞,NOV基因对其发育分化的作用如何,尚未见有文献报道,是一个值得探讨的向题。Marian Zaka(2005)及Shuying Lin(2005)先后报告IGF-1具有促OPCs增殖和减少其毒性物质诱发OPCs的凋亡,从而改善缺血缺氧所致的脑白质损伤。既然NOV基因是动物神经系统发育、再生的重要调控因子,IGF系其编码结合蛋白,将其应用于OPCs的研究,可以观察其对OPCs发育分化及缺血、缺氧性白质损伤的作用。
本实验分为三个部分：
第一部分：
运用PDGFaR抗体来分析生后大鼠脑中OPCs的形态、分布和密度等发育规律,同时观察其电生理特征。结合以前的研究报道与NG2+细胞进行比较,同时,对不同发育时期的不同脑区应用相邻切片进行PDGFaR和NG2的免疫荧光染色,比较PDGFaR+和NG2+的细胞密度的变化与脑发育的相关性。期望这些数据能够帮助我们对中枢神经系统中OPCs的生物学特性有进一步的了解。
主要结果如下：
1、大鼠中枢神经系统PDGFaR+OPCs在形态、分布、密度的发育规律及电生理学特性等方面与NG2+OPCs高度相似。
2、老年大鼠脑中有约25%的NG2+OPCs表达PDGFaR阴性,但是在形态上与NG2+/PDGFaR+OPCs相似。
3、老化对OPCs的形态、数量和发育调控有影响。
上述结果表明PDGFaR和NG2都是OPCs的标记物。PDGFaR主要在发育的未成熟前体细胞上表达。而在少突胶质细胞成熟前期,PDGFaR的表达已经消失,而NG2还在持续表达。NG2免疫阳性细胞可能不同于传统意义上的少突胶质前体细胞,而是一种成熟的胶质细胞。
第二部分：
联合应用耗氧剂和无糖培养基在常氧培养条件下建立新生未成熟大鼠少突胶质前体细胞缺氧缺糖模型,并观察缺氧缺糖对细胞形态和存活率的影响。同时,利用P4大鼠左侧颈总动脉结扎后吸入8%氧气2小时建立新生大鼠脑缺血缺氧模型,观察脑组织病理学改变、MBP和PDGFaR的表达情况。评估离体与在体少突胶质前体细胞缺血缺氧模型是否有效。
主要结果如下：
1、联合应用无糖DMEM培养基和连二亚硫酸钠后,培养OPCs出现明显的形态学改变,细胞突起肿胀、变形、断裂,细胞水肿,并随时间延长而加剧。少突胶质前体细胞存活率随缺氧缺糖时间的延长而逐渐下降,30min、60min和90min细胞存活率均明显低于正常对照组,差异有统计学意义(P均<0.05)。
2、P4大鼠左侧颈总动脉结扎后吸入8%氧2小时,脑组织发生病理学改变；神经细胞凋亡数量增加；MBP、NF200和PDGFaR的表达均下降。
上述结果表明利用无糖培养基和连二亚硫酸钠可以在常氧培养条件下建立体外培养的少突胶质前体细胞缺氧缺糖模型。利用P4大鼠左侧颈总动脉结扎后吸入8%氧气2小时可建立新生大鼠脑缺血缺氧模型。应用这两种在体与离体模型,可模拟缺氧缺血对新生儿大脑造成的损伤。
第三部分：
将NOV cDNA全长序列克隆到pEGFP-N1真核表达质粒上,再将重组质粒转染到COS-7细胞中,用免疫细胞化学技术和Western Blot方法检测NOV的表达。收集培养NOV/COS-7细胞的条件培养液(NOV-CM),观察NOV基因对缺血缺氧脑损伤模型中OPCs增殖和分化的影响以及能否促进神经损伤的修复。
主要结果如下：
1、利用RT-PCR的产物,采用定向克隆的方法,成功地将NOV cDNA全长序列克隆到pEGFP-N1真核表达质粒上,对克隆的cDNA片段进行核酸测序,证明获得的重组子完全符合设计要求。在此基础上,将重组质粒转染到COS-7细胞中,用免疫细胞化学技术和Western Blot方法检测到COS-7细胞与COS-7细胞的培养上清液中均有NOV的表达。
2、在构建了NOV基因真核表达载体的基础上,将载体转染到COS-7细胞中,收集NOV/COS-7细胞上清液(NOV-CM),对少突胶质前体细胞缺血缺氧离体与在体模型进行治疗。结果发现其NOV-CM不仅对OPCs缺血缺氧损伤具有一定的保护作用,并对神经元和髓鞘的损伤修复有促进。结果提示NOV基因有可能具有保护神经损伤后再生和功能重建的作用,为临床治疗缺氧缺血脑损伤提供了线索。
Oligodendrocyte progenitor cells (OPCs) have the capability of self-renewal and unsymmetrical differentiation in vitro, which are identified as multi-potent progenitor cells or intrinsic CNS adult stem cells. OPCs express several markers, such as NG2, the platelet-derived growth factor-a receptor (PDGFaR) and 04. Thus far, studies have provided abundant evidence that OPCs are highly reactive cells that respond to several types of nerve injuries, such as viral infection, immune reaction, nerve degenerative disease, CO-induced demyelination, dysbolism and Hypoxic-ischemic encephalopathy. OPCs belonged to oligodendrocyte lineage. But if the only function of OPCs was differentiated into oligodendrocyte? OPCs was upregulated as a result of physical, viral, excitotoxic and inflammatory insults to the CNS. Following demyelination OPCs number increaseed in the immediate vicinity of the lesion and rapid remyelination ensues, which was different from astrocyte and microglia. The number and immune reaction of OPCs increased after nerve degenerative disease. The direct evidence that OPCs can repair the damage and promote myelogeny was poor. The study of cytobiology and electrophysiological characteristics of OPCs were deficiency too. But the effects of OPCs on the development, differentiation and regenerationon in central nervous system was not clear.
Perinatal hypoxia-ischemia (HI) is a significant primary cause of brain damage of neonates. Periventricular white matter injury (PWMI) is the predominant form of brain injury underlying this neurological morbidity. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and focal, multifocal, or diffuses myelination disturbances. Despite major advances in obstetric and perinatal medicine, there has been little chang in the incidence of hypoxic-ischemic encephalopathy, which has been estimated to occur in approximately 3-4 neonates per 1000 live-born at term, the incidence is higher in small preterm neonates. Depending on the gestational age and the severity of the insult, between 10% and 60% of asphyxiated neonates who have hypoxic-ischemic encephalopathy expire during the neonatal period and 25% or more of the survivors develop permanent neuropsychological deficits such as cerebral palsy, mental retardation and epilepsy. OPCs have been demonstrated to be intrinsically more vulnerable to injury than mature oligodendrocytes under conditions of oxidative stress, oxygen glucose deprivation (OGD) in vitro, hypoxia-ischemia in vivo (Back et al.,2002), and glutamate receptor-mediated excitotoxicity. Perinatal hypoxia-ischemia (HI) is a significant primary cause of PWMI. The fact that OPCs appear coinciding with the high-risk period for PWMI and is selectively targeted by HI suggests that OPCs are the major target cell of injury in PWMI. However, Our understanding of the fundamental mechanisms involved in selective injury of OPCs to HI in the developing brain is still limited.
Nephroblastoma Overexpression gene, abbreviated as NOV, is a proto-oncogene, which was discovered in 1991. NOV protein, which is encoded by NOV gene, is a kind of insulin-like growth factor (IGF) binding protein (IGFBP), and one of the families of IGF. NOV gene is a multipurpose factor that regulates cell proliferation. IGF-I was necessary for the proliferation of the nerve stem cells, which could affect the nerve stem cells through tyrosine protein kinase pathway. bFGF and EGF couldn't stimulate the proliferation of the nerve stem cells. The effect of NOV on the development and differentiation of OPCs is unknow. Marian Zaka and Shuying Lin found that IGF-1 could promote the proliferation of OPCs and decrease the apoptosis of OPCs induced by Toxic substance. Since NOV was the important regulating factor of nerve system development and regeneration, and IGF was the encode binding protein, we want to see if the NOV have the effects on promoting the regeneration and function recovery of OPCs after OGD. Therefore, this investigate is divided into three part:
Part 1:
We use PDGFaR antibody to analyze the developmental regulation of PDGFaR+ cells in the normal postnatal rats CNS from birth to old age, including the morphology, distribution, growth characteristics and the quantity of PDGFaR+ cells population. Meantime, double labelling with antibodies against PDGFaR and NG2 is applied and the results compare to the different developmental stage. It is expected these data will help us to find out the developmental regulation of the PDGFaR+ OPCs and compare to the NG2+ OPCs in the CNS as well as the primary significance of co-localization to the OPCs developmental lineage.
The main results are as following:
1. The morphology, distribution, electrophysiological characteristics and developmental regulation of PDGFaR+ cells in rat CNS are similar to that of NG2+ cells.
2. The number of PDGFαR+ cells at early developmental stages is much more than that at later stages. Specifically at the later postnatal stages,25% of the NG2+ cells do not express PDGFαR and the morphology of PDGFαR-/NG2+ cells is similar to that of NG2+ cells.
3. Aging has an effect on the morphological feature, number and developmental regulation of OPCs in rat CNS.
In conclusion, both PDGFαR and NG2 are markers of developing OPCs. PDGFαR expression is seen on the most developing and immature precursors, then the cells acquiring NG2 expression as they mature. At the preoligodendrocyte stage, PDGFαR expression has ceased, whereas NG2 expression persists, at least at the beginning of this stage. NG2+ cells may be a mature glial cell type distinct from conventional OPCs.
Part 2:
To establish an oxygen/glucose derived(OGD) model of SD rat's oligodendrocyte precursor cells in a nomaxic environment in vitro with dithionite sodium and DMEM without glucose, and evaluate the model by investigating to the changes of cellular shapes and survival caused by OGD. And 4-day-old SD rats were anesthetized and subjected to a hypoxic/ischemic injury obtained by combination of monolateral carotid ligation and exposure to 8% oxygen for 2h. Histopathologic changes and the express of MBP and PDGFαR were observed to evaluate the model.
The main results are as following:
1. When the PDGFaR positive OPCs were cultured with sodium dithonite and DMEM without glucose, the morphologic changes were obvious:cell body swelling and the processes swelling, deformed and collapsed gradually. The survival rate decreases gradually with the time and the rate was about 50% at 60 min while it decreased to a level lower than 50% at 90min.
2. After a hypoxic/ischemic injury obtained by combination of monolateral carotid ligation and exposure to 8% oxygen for 2h, the histological damage was observed and the numbers of the apoptotic nerve cells increased. The express of MBP、NF200 and PDGFαR decreased.
The second part revealed that DMEM without glucose and sodium dithionite can be applied to the construction of GOD model in PDGFaR positive oligodendrocytes in a normoxic incubator in vitro. The damages of oligodendrocyte precursor cells caused by hypoxia-ischemia in vitro can be analogized with this model, and similar damages occur in the oligodendrocyte precursor cell in vitro.
Part 3:
We built pEGFP-N 1 vector containing NOV gene complete sequence to transfer, and examined its expression by immunohistochemisty and conditioned medium (CM) from cultured NOV/COS-7 cells (NOV-CM) was collected. The effects of NOV on the proliferation and differentiation of OPCs were studied and see if the COS7s engineered by NOV gene have the effects of promoting the regeneration and function recovery of nerve injury.
The main results are as following:
1. The NOV gene complete sequence were synthesized by RT-PCR, and ligated into EcoR I and Hind III sites of pEGFP-Nl vector. The nucleotide sequences of the cDNA were determined. The vector was led into cultured COS-7 cells using DOTAP liposomal transfection reagent. The expression of NOV protein was detected by Western blot and immunocytochemistry.
2. We built pEGFP-N1 vector containing NOV gene complete sequence and conditioned medium (CM) from cultured NOV/COS-7 cells (NOV-CM) was collected. NOV-CM was treated to the OPCs of OGD. Results showed NOV gene promoted the survival of OPCs and the recovery of structure and function of neuron and myelin after injury. Our results indicated that NOV gene probably involved in the processs of repair of nerve injury and rebuilding of function. The results of this study provide some fundmental information for the clinical application of OGD.
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