电离辐射后少突胶质细胞基因表达谱改变的实验研究
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摘要
在大脑、头颈部肿瘤和一些颅内良性疾病的治疗中,大脑和脊髓等重要的剂量限制性器官往往会临近或位于射野范围之内,放射治疗后除了部分病人死于肿瘤局部未控之外,约有50%的长期生存患者会发生不同程度的放射性后遗症,其中以放射性脑或脊髓损伤的病情较为严重,患者的生活质量明显降低。基于以上原因,中枢神经系统(central nervous system, CNS)的电离辐射效应的研究已经全面展开。目前对于放射性脑损伤发病机理和早期诊断的研究还相对较少,至今仍无有效的早期诊断和治疗措施,所以这些研究工作对肿瘤放射治疗学的发展有着重要的理论意义和应用价值。
病理学改变的研究表明,早期脑损伤以血管系统变化为主,没有特异性;晚期则出现较典型的脱髓鞘、胶质细胞增生与退行性改变、毛细血管阻塞和白质坏死等四大特征。由于血管损伤的广泛性和少突胶质细胞(oligodendrocyte, OL)是CNS中唯一能合成髓鞘的细胞,因此血管内皮细胞和OL被确立为放射性脑损伤的辐射靶细胞,OL成为发病机理研究的重点之一。随着研究的深入,目前认为主要有四种因素参与了放射性脑损伤的发生与发展,其分别是:血管损伤、少突胶质前体细胞及成熟OL耗竭、神经干细胞减少和细胞因子表达异常。
近几年来,关于OL方面的研究大多集中于细胞和分子水平,主要内容包括电离辐射后OL的凋亡及其发生机制、少突胶质前体细胞和成熟OL的辐射反应性以及辐射剂量与分割方式影响等方面。然而,对于OL的研究没有与发生放射性脱髓鞘病变机制形成密切的相关性;早期和亚急性期细胞、分子反应的特性与晚期损伤病理学改变的关系仍不清楚。在神经病学和神经生物学领域的研究中,有许多关于“OL损伤”和“脱髓鞘病变”的文献报道,脱髓鞘是普遍的或特征性的病变,OL也被证实是多种致病因素(外伤、缺血、缺氧和异常免疫反应等)易受攻击的靶细胞。目前的研究表明少突胶质细胞系各阶段的特异性标志分子已基本明确,可以通过不同标记物的组合来区分它们;少突胶质-2型星形胶质前体细胞(oligodendrocyte-type 2 astrocyte progenitor cells, O2A)离体培养的成功也为研究其增殖、迁徙、分化特性及与脱髓鞘病变的关系提供了实验细胞模型;在正常成年大脑与脊髓内存在着约占胶质细胞5~8%的具有分化潜能的前体细胞,一定程度的损伤性刺激后可以使它们发生增殖、迁徙、分化和再生,这为神经损伤的治疗提供了新的思路。
一、少突胶质细胞纯化培养的实验研究
目的获得芯片检测所需要的纯化OL。
方法采用改良的恒温振荡、差速贴壁法进行O2A的纯化培养,并通过体外诱导分化使之为成熟的OL;应用免疫荧光双重标记方法进行OL的细胞鉴定。
结果OL免疫荧光标记为A2B5标记阴性、MBP或GalC标记阳性;OL纯度达98%,且细胞数量达到5×106个。
二、电离辐射后少突胶质细胞基因表达谱变化的离体实验
目的观察电离辐射前后OL基因表达的早期变化规律。
方法对纯化的OL采用6MV-X线照射10Gy剂量,用表达谱芯片检测比较对照组(1组)与照射后1hr、4hr组(2、3组)各基因mRNA表达的变化。
结果三组细胞杂交后的基因检出率分别为42.81%、41.64%、45.31%;2比1上调基因数为27个,下调基因数为164个,3比1上调基因数为295个,下调基因数为302个,3比2上调基因数为510个,下调基因数为320个;基因功能分类结果共有79大类1079个基因被列出,具体功能分类包括:细胞生理过程、肿瘤凋亡、新陈代谢、细胞周期、细胞通讯、蛋白结合等。
三、与早期放射性脑损伤相关的功能基因定量分析
目的验证芯片结果可靠性的同时进一步探讨候选基因在OL内差异表达的意义。
方法依据芯片检测结果选出9个在早期放射性脑损伤中可能发挥重要调控作用的候选基因,应用实时荧光定量RT-PCR的方法对其mRNA进行定量分析。
结果荧光定量RT-PCR基因定量与基因芯片分析结果比较,27个mRNA检测结果中有22个结果一致,符合率为81.5%;三组样本中各基因ΔCt值分别为:①胶质原纤维酸性蛋白:1.3777、2.2266、5.3992;②髓鞘碱性蛋白:-3.4061、-2.6133、-2.0232;③载脂蛋白E:12.1203、14.7452、17.2264;④促甲状腺激素释放激素:5.8994、8.2740、2.4709;⑤甲状腺激素受体α:6.3269、5.8081、6.4793;⑥转化生长因子β2:4.6782、5.2108、5.1181;⑦早期生长反应2:10.0840、7.4766、8.5754;⑧神经细胞黏附分子1:3.7024、3.9211、5.6716;⑨S100蛋白β多肽:2.5607、5.5696、4.2581。
结论
1.通过改良的恒温振荡法和差速贴壁法进行O2A的纯化培养,并诱导分化为纯化的OL,免疫荧光标记为A2B5标记阴性、MBP或GalC标记阳性;OL纯度达98%,且细胞数量达到5×106个,符合基因芯片检测要求。
2.照射后早期就发生了电离辐射导致的OL基因表达谱的改变;芯片检测结果提示发生变化的OL基因包括细胞损伤相关基因、细胞保护相关基因和损伤修复相关基因,这些基因之间的动态平衡变化决定了辐射对OL的最终生物学效应。
3.应用实时荧光定量RT-PCR的方法对候选基因mRNA进行定量分析,结果与芯片检测基因mRNA的结果基本一致,两者比较在检测的特异性上更加近似,而检测的敏感性上前者优于后者;对候选基因mRNA进行定量分析,进一步了解了它们在放射性脑损伤早期的变化情况,GFAP、MBP、apoE、TGFβ2和NCAM-1 mRNA下调的变化可能与OL的损伤机制相关;而TRH、THRα和EGR2 mRNA上调以及S100βmRNA下调的变化可能与OL的修复与保护机制相关。
Ionizing radiation remains a major treatment modality for primary and metastatic tumors of the central nervous system (CNS) and the head-neck. In addition, application of radiation in some other nonneoplastic disorders of the brain is increasing. In the treatment of tumors within or adjacent to the brain and spinal cord, this complications is associated with a high risk of morbidity, which can be especially devastating to patients. For this reason, this effect of radiation on the CNS has been the basis for extensive research. The pathogenesis and the early stage diagnosis of the radiation-induced CNS injury were insufficient at the present time. Studying extensively will be significantly to the development of radiation oncology.
Pathological analysis of radiation-induced CNS injury confirmed that vascular abnormalities appeared atypical in the early stage. Late changes of the brain can be distinguished: Demyelination, proliferative and degenerative glial reactions, capillary occlusion and white matter necrosis. Because vascular abnormalities and demyelination dominate the histological presentation of radiation injury in the CNS, the vasculature and the oligodendrocytes lineage have traditionally been considered the primary radiation targets in the CNS. With the development of these research works, at least four factors contribute to the development of CNS toxicity: Damage to vessel structures; deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; generalized alterations of cytokine expression.
Both recent laboratory and clinical data have been used to establish the mechanisms of oligodendrocytes apoptosis, radiation effects of O-2A and mature oligodendrocytes, the response to dose per fraction and number of fractions. In contrast, the relationships between the radiation response to oligodendrocytes and the mechanisms of demyelination remain unclear. The cellular and molecular processes responsible for the histological presentation of radiation induced CNS injury remain poorly defined. There are a lot of reports in neurological and neurobiological research that oligodendrocytes were also targets of injury in several pathological conditions, such as trauma, ischemia, hypoxia, abnormal immune reaction. Recent studies indicated that the oligodendrocytes lineage express the cell-specific antigens in the specific stage. The methods have been established to obtaining more pure O-2A progenitor cells. After pathological stimulation these O-2A progenitor cells were proliferated, migrated and differentiated, which provided new avenues to explore the new therapy strategy for the CNS injury.
PartⅠThe method for culture of rats’pure oligodendrocytes
Objective To establish the method of obtaining more pure O-2A progenitor cells, so as to build oligodendrocytes culture for subsequentant microarray research.
Methods Based on the differential properties of cellular adhesions and developmental time–course, O-2A progenitor cells were isolated at the onset of the layer of T1A with a standard shaking method and then purified with the differential adhesion method combining with using the growth factors, and further O-2A progenitor cells differentiated into oligodendrocytes depending on the culture medium. Immunocytochemistry labeling for cell-specific antigens had been done to characterize oligodendrocytes.
Results The mature oligodendrocytes expressed MBP or GalC, whereas did not express the A2B5 antigens. The purity of oligodendrocytes was 98% and the quantities were 5×106.
PartⅡEarly gene expression profile in oligodendrocytes after exposure to ionizing radiation in vitro
Objective To characterize the cellular functions associated with the altered transcript profiles of oligodendrocytes exposed to in vitro X-ray irradiation.
Methods The total RNA was extracted from oligodendrocytes in unirradiated control (Group 1) and at 1 hour (Group 2), 4 hour (Group 3) after 6MV X-ray irradiation at 10Gy, hybridized to Affymetrix RAT230 2.0 Array, and evaluated the difference and screening the genes expressed differently.
Results The expression rate of gene chips in three groups was 42.81%, 41.64% and 45.31% respectively. The genes with 2-fold expressed differentially include 27 genes up-regulated and 164 genes down-regulated in Group 2 vs. Group 1, 295 genes up-regulated and 302 genes down-regulated in Group 3 vs. Group 1, 510 genes up-regulated and 320 genes down-regulated in Group 3 vs. Group 2. According to functional categories results, there were 1079 genes expressed. The numbers of functional classification were 79. The annotated genes functional classification was associated with oligodendrocytes injury, repair and protection, such as cellular physiological process, apoptosis or tumor, cell cycle, metabolism, cell communication, receptor binding, et al.
PartⅢReal-time RT-PCR analysis of functional gene expression in early radiation-induced CNS injury
Objective To validate the microarray results and discuss these significantly modulated genes in oligodendrocytes.
Methods Quantitative real-time RT-PCR was performed to analysis 9 genes mRNA for selected radiation-modulated genes.
Results Comparing with the results between the mircoarray and the real-time RT-PCR, the coincidence rate was 81.5%.ΔCt value of 9 genes included:①glial fibrillary acidic protein: 1.3777, 2.2266, 5.3992;②myelin basic protein: -3.4061, -2.6133, -2.0232;③apolipoprotein E: 12.1203, 14.7452, 17.2264;④thyrotropin releasing hormone: 5.8994, 8.2740, 2.4709;⑤thyroid hormone receptorα: 6.3269, 5.8081, 6.4793;⑥transforming growth factor, beta 2: 4.6782, 5.2108, 5.1181;⑦early growth response 2: 10.0840, 7.4766, 8.5754;⑧neural cell adhesion molecule 1: 3.7024, 3.9211, 5.6716;⑨S100 protein, beta polypeptide: 2.5607, 5.5696, 4.2581.
Conclusions
1. Pure oligodendrocytess expressed MBP or GalC positive and A2B5 negative epitope. The purity and the quantities matched the criterion of microarray.
2. Radiation-induced changes in oligodendrocytes gene expression took place early after irradiation. The findings suggest that irradiation of the oligodendrocytes induced the expression of genes involved in damaging, protective and reparative functions, while the dynamic balance of these modulated gene decided the ultimate radiation-induced pathophysiological effects.
3. The results of real-time RT-PCR coincided with the results of microarray. Both of them were approximate in the testing particularity, while real-time RT-PCR was superior to microarray in the testing sensitivity. These real-time RT-PCR results revealed that gene expression changed during the early radiation-induced CNS injury, and that, down-modulating GFAP, MBP, apoE, TGFβ2, NCAM-1 mRNA coincided with the mechanisms of the oligodendrocytes damaging, while up-modulating TRH, THRα, EGR2 mRNA and down-modulating S100βmRNA coincided with the mechanisms of the oligodendrocytes protective and reparative functions.
病理学改变的研究表明,早期脑损伤以血管系统变化为主,没有特异性;晚期则出现较典型的脱髓鞘、胶质细胞增生与退行性改变、毛细血管阻塞和白质坏死等四大特征。由于血管损伤的广泛性和少突胶质细胞(oligodendrocyte, OL)是CNS中唯一能合成髓鞘的细胞,因此血管内皮细胞和OL被确立为放射性脑损伤的辐射靶细胞,OL成为发病机理研究的重点之一。随着研究的深入,目前认为主要有四种因素参与了放射性脑损伤的发生与发展,其分别是:血管损伤、少突胶质前体细胞及成熟OL耗竭、神经干细胞减少和细胞因子表达异常。
近几年来,关于OL方面的研究大多集中于细胞和分子水平,主要内容包括电离辐射后OL的凋亡及其发生机制、少突胶质前体细胞和成熟OL的辐射反应性以及辐射剂量与分割方式影响等方面。然而,对于OL的研究没有与发生放射性脱髓鞘病变机制形成密切的相关性;早期和亚急性期细胞、分子反应的特性与晚期损伤病理学改变的关系仍不清楚。在神经病学和神经生物学领域的研究中,有许多关于“OL损伤”和“脱髓鞘病变”的文献报道,脱髓鞘是普遍的或特征性的病变,OL也被证实是多种致病因素(外伤、缺血、缺氧和异常免疫反应等)易受攻击的靶细胞。目前的研究表明少突胶质细胞系各阶段的特异性标志分子已基本明确,可以通过不同标记物的组合来区分它们;少突胶质-2型星形胶质前体细胞(oligodendrocyte-type 2 astrocyte progenitor cells, O2A)离体培养的成功也为研究其增殖、迁徙、分化特性及与脱髓鞘病变的关系提供了实验细胞模型;在正常成年大脑与脊髓内存在着约占胶质细胞5~8%的具有分化潜能的前体细胞,一定程度的损伤性刺激后可以使它们发生增殖、迁徙、分化和再生,这为神经损伤的治疗提供了新的思路。
一、少突胶质细胞纯化培养的实验研究
目的获得芯片检测所需要的纯化OL。
方法采用改良的恒温振荡、差速贴壁法进行O2A的纯化培养,并通过体外诱导分化使之为成熟的OL;应用免疫荧光双重标记方法进行OL的细胞鉴定。
结果OL免疫荧光标记为A2B5标记阴性、MBP或GalC标记阳性;OL纯度达98%,且细胞数量达到5×106个。
二、电离辐射后少突胶质细胞基因表达谱变化的离体实验
目的观察电离辐射前后OL基因表达的早期变化规律。
方法对纯化的OL采用6MV-X线照射10Gy剂量,用表达谱芯片检测比较对照组(1组)与照射后1hr、4hr组(2、3组)各基因mRNA表达的变化。
结果三组细胞杂交后的基因检出率分别为42.81%、41.64%、45.31%;2比1上调基因数为27个,下调基因数为164个,3比1上调基因数为295个,下调基因数为302个,3比2上调基因数为510个,下调基因数为320个;基因功能分类结果共有79大类1079个基因被列出,具体功能分类包括:细胞生理过程、肿瘤凋亡、新陈代谢、细胞周期、细胞通讯、蛋白结合等。
三、与早期放射性脑损伤相关的功能基因定量分析
目的验证芯片结果可靠性的同时进一步探讨候选基因在OL内差异表达的意义。
方法依据芯片检测结果选出9个在早期放射性脑损伤中可能发挥重要调控作用的候选基因,应用实时荧光定量RT-PCR的方法对其mRNA进行定量分析。
结果荧光定量RT-PCR基因定量与基因芯片分析结果比较,27个mRNA检测结果中有22个结果一致,符合率为81.5%;三组样本中各基因ΔCt值分别为:①胶质原纤维酸性蛋白:1.3777、2.2266、5.3992;②髓鞘碱性蛋白:-3.4061、-2.6133、-2.0232;③载脂蛋白E:12.1203、14.7452、17.2264;④促甲状腺激素释放激素:5.8994、8.2740、2.4709;⑤甲状腺激素受体α:6.3269、5.8081、6.4793;⑥转化生长因子β2:4.6782、5.2108、5.1181;⑦早期生长反应2:10.0840、7.4766、8.5754;⑧神经细胞黏附分子1:3.7024、3.9211、5.6716;⑨S100蛋白β多肽:2.5607、5.5696、4.2581。
结论
1.通过改良的恒温振荡法和差速贴壁法进行O2A的纯化培养,并诱导分化为纯化的OL,免疫荧光标记为A2B5标记阴性、MBP或GalC标记阳性;OL纯度达98%,且细胞数量达到5×106个,符合基因芯片检测要求。
2.照射后早期就发生了电离辐射导致的OL基因表达谱的改变;芯片检测结果提示发生变化的OL基因包括细胞损伤相关基因、细胞保护相关基因和损伤修复相关基因,这些基因之间的动态平衡变化决定了辐射对OL的最终生物学效应。
3.应用实时荧光定量RT-PCR的方法对候选基因mRNA进行定量分析,结果与芯片检测基因mRNA的结果基本一致,两者比较在检测的特异性上更加近似,而检测的敏感性上前者优于后者;对候选基因mRNA进行定量分析,进一步了解了它们在放射性脑损伤早期的变化情况,GFAP、MBP、apoE、TGFβ2和NCAM-1 mRNA下调的变化可能与OL的损伤机制相关;而TRH、THRα和EGR2 mRNA上调以及S100βmRNA下调的变化可能与OL的修复与保护机制相关。
Ionizing radiation remains a major treatment modality for primary and metastatic tumors of the central nervous system (CNS) and the head-neck. In addition, application of radiation in some other nonneoplastic disorders of the brain is increasing. In the treatment of tumors within or adjacent to the brain and spinal cord, this complications is associated with a high risk of morbidity, which can be especially devastating to patients. For this reason, this effect of radiation on the CNS has been the basis for extensive research. The pathogenesis and the early stage diagnosis of the radiation-induced CNS injury were insufficient at the present time. Studying extensively will be significantly to the development of radiation oncology.
Pathological analysis of radiation-induced CNS injury confirmed that vascular abnormalities appeared atypical in the early stage. Late changes of the brain can be distinguished: Demyelination, proliferative and degenerative glial reactions, capillary occlusion and white matter necrosis. Because vascular abnormalities and demyelination dominate the histological presentation of radiation injury in the CNS, the vasculature and the oligodendrocytes lineage have traditionally been considered the primary radiation targets in the CNS. With the development of these research works, at least four factors contribute to the development of CNS toxicity: Damage to vessel structures; deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; generalized alterations of cytokine expression.
Both recent laboratory and clinical data have been used to establish the mechanisms of oligodendrocytes apoptosis, radiation effects of O-2A and mature oligodendrocytes, the response to dose per fraction and number of fractions. In contrast, the relationships between the radiation response to oligodendrocytes and the mechanisms of demyelination remain unclear. The cellular and molecular processes responsible for the histological presentation of radiation induced CNS injury remain poorly defined. There are a lot of reports in neurological and neurobiological research that oligodendrocytes were also targets of injury in several pathological conditions, such as trauma, ischemia, hypoxia, abnormal immune reaction. Recent studies indicated that the oligodendrocytes lineage express the cell-specific antigens in the specific stage. The methods have been established to obtaining more pure O-2A progenitor cells. After pathological stimulation these O-2A progenitor cells were proliferated, migrated and differentiated, which provided new avenues to explore the new therapy strategy for the CNS injury.
PartⅠThe method for culture of rats’pure oligodendrocytes
Objective To establish the method of obtaining more pure O-2A progenitor cells, so as to build oligodendrocytes culture for subsequentant microarray research.
Methods Based on the differential properties of cellular adhesions and developmental time–course, O-2A progenitor cells were isolated at the onset of the layer of T1A with a standard shaking method and then purified with the differential adhesion method combining with using the growth factors, and further O-2A progenitor cells differentiated into oligodendrocytes depending on the culture medium. Immunocytochemistry labeling for cell-specific antigens had been done to characterize oligodendrocytes.
Results The mature oligodendrocytes expressed MBP or GalC, whereas did not express the A2B5 antigens. The purity of oligodendrocytes was 98% and the quantities were 5×106.
PartⅡEarly gene expression profile in oligodendrocytes after exposure to ionizing radiation in vitro
Objective To characterize the cellular functions associated with the altered transcript profiles of oligodendrocytes exposed to in vitro X-ray irradiation.
Methods The total RNA was extracted from oligodendrocytes in unirradiated control (Group 1) and at 1 hour (Group 2), 4 hour (Group 3) after 6MV X-ray irradiation at 10Gy, hybridized to Affymetrix RAT230 2.0 Array, and evaluated the difference and screening the genes expressed differently.
Results The expression rate of gene chips in three groups was 42.81%, 41.64% and 45.31% respectively. The genes with 2-fold expressed differentially include 27 genes up-regulated and 164 genes down-regulated in Group 2 vs. Group 1, 295 genes up-regulated and 302 genes down-regulated in Group 3 vs. Group 1, 510 genes up-regulated and 320 genes down-regulated in Group 3 vs. Group 2. According to functional categories results, there were 1079 genes expressed. The numbers of functional classification were 79. The annotated genes functional classification was associated with oligodendrocytes injury, repair and protection, such as cellular physiological process, apoptosis or tumor, cell cycle, metabolism, cell communication, receptor binding, et al.
PartⅢReal-time RT-PCR analysis of functional gene expression in early radiation-induced CNS injury
Objective To validate the microarray results and discuss these significantly modulated genes in oligodendrocytes.
Methods Quantitative real-time RT-PCR was performed to analysis 9 genes mRNA for selected radiation-modulated genes.
Results Comparing with the results between the mircoarray and the real-time RT-PCR, the coincidence rate was 81.5%.ΔCt value of 9 genes included:①glial fibrillary acidic protein: 1.3777, 2.2266, 5.3992;②myelin basic protein: -3.4061, -2.6133, -2.0232;③apolipoprotein E: 12.1203, 14.7452, 17.2264;④thyrotropin releasing hormone: 5.8994, 8.2740, 2.4709;⑤thyroid hormone receptorα: 6.3269, 5.8081, 6.4793;⑥transforming growth factor, beta 2: 4.6782, 5.2108, 5.1181;⑦early growth response 2: 10.0840, 7.4766, 8.5754;⑧neural cell adhesion molecule 1: 3.7024, 3.9211, 5.6716;⑨S100 protein, beta polypeptide: 2.5607, 5.5696, 4.2581.
Conclusions
1. Pure oligodendrocytess expressed MBP or GalC positive and A2B5 negative epitope. The purity and the quantities matched the criterion of microarray.
2. Radiation-induced changes in oligodendrocytes gene expression took place early after irradiation. The findings suggest that irradiation of the oligodendrocytes induced the expression of genes involved in damaging, protective and reparative functions, while the dynamic balance of these modulated gene decided the ultimate radiation-induced pathophysiological effects.
3. The results of real-time RT-PCR coincided with the results of microarray. Both of them were approximate in the testing particularity, while real-time RT-PCR was superior to microarray in the testing sensitivity. These real-time RT-PCR results revealed that gene expression changed during the early radiation-induced CNS injury, and that, down-modulating GFAP, MBP, apoE, TGFβ2, NCAM-1 mRNA coincided with the mechanisms of the oligodendrocytes damaging, while up-modulating TRH, THRα, EGR2 mRNA and down-modulating S100βmRNA coincided with the mechanisms of the oligodendrocytes protective and reparative functions.
引文
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