干细胞因子对不同分化状态下神经干细胞迁移的影响
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摘要
胶质瘤是一种常见的颅内恶性肿瘤,因其呈侵染性生长,使得手术切除辅以化疗、放疗的传统方法往往难以将其根治,致死率极高。近年来体内外的研究证明,胶质瘤细胞能够诱导神经干细胞(neural stem cells, NSCs)的迁移,为神经胶质瘤的治疗带来了希望。然而胶质瘤诱导NSCs迁移的细胞与分子机制并不明确,尤其是不同分化状态的NSCs与其迁移行为的关系还鲜有报道。本实验主要就该问题展开进一步的研究。
本研究首先从新生远交群(Sprague Dawley, SD)大鼠侧脑室外侧壁的脑室下区(the subventricular zone, SVZ)中分离并纯化出NSCs,用含1%胎牛血清的H-DMEM进行诱导分化,并通过对细胞形态、生长特性及特异性抗原(nestin、GFAP和β-III-tubulin)表达对细胞进行了鉴定。结果表明,SVZ区域来源的NSCs呈nestin阳性,更换分化诱导液后能分化成神经元(β-III-tubulin+)和星形胶质细胞(GFAP+)。
随后选取生长第4～5天的NSCs,更换含不同浓度干细胞因子(stem cell factor, SCF)的分化培养基对NSCs进行处理。通过延时动态视频(time-lapse video)跟踪观察NSCs分化0-48 h的不同阶段下对SCF的刺激做出应答时其迁移行为发生了哪些变化。含不同浓度SCF的分化诱导液对NSCs处理后结果表明,与对照组相比,5 ng/ml的SCF未能对分化0-12 h及36-48 h内的NSCs的迁移距离产生影响,但显著提高了分化12-36 h内NSCs的迁移距离。而25 ng/ml的SCF在分化0-36 h内的迁移距离显著高于对照组但未能对分化36-48 h内NSCs的迁移距离产生影响,并且仅在分化0-12 h内NSCs的迁移距离显著高于5 ng/ml的SCF。与此同时,与对照组相比,5 ng/ml的SCF显著提高了分化0-36 h内NSCs的迁移效率(forward migration index, FMI),但未能影响分化36-48 h内的FMI。而25 ng/ml的SCF在分化0-48 h内的迁移效率显著高于对照组,而且在分化的36-48 h内显著高于5 ng/ml的SCF实验组,但在分化0-36 h内两实验组无显著差异。这些现象表明,NSCs的迁移行为与其所处的分化状态有着紧密的内在联系。
为了进一步验证前期的实验结果并为后期的体内等机理性研究做准备,我们选择了C17.2神经干细胞系,运用Boyden chamber及Dunn chamber来研究SCF诱导C17.2神经干细胞的趋化性迁移。Boyden chamber结果显示,下室加入SCF后迁移至膜下方的C17.2细胞数显著多于对照组。在C17.2分化24 h时其对SCF的应答最强,定向迁移的细胞数要明显多于未分化状态。而随着分化进程的深入,其迁移能力逐渐降低,到第7 d时已显著低于未分化状态。Dunn chamber结果显示,仅在外槽加入SCF的C17.2细胞迁移速率及迁移效率显著高于内外槽均加入SCF的细胞,单个细胞迁移轨迹分析表明仅在外槽加入SCF后细胞朝着浓度梯度方向迁移而内外槽均加入SCF后细胞的迁移则无规律。用LY294002阻断PI3K通路后,C17.2细胞向SCF迁移的速率显著降低,但并未影响其定向迁移能力。这些结果表明,SCF通过影响C17.2细胞的迁移速率及迁移效率来影响C17.2细胞的定向迁移,PI3K信号通路参与了此过程;而且不同分化阶段的C17.2细胞对SCF的响应能力不同,为进一步了解神经干细胞定向追踪胶质瘤提供了理论依据。
Rac亚家族中Rac1的功能一直以来都是研究的热点。Rac1蛋白具有活性Rac1-GTP和非活性Rac1-GDP两种状态,当Rac1被激活后,可参与肌动蛋白应力纤维和粘附斑形成,促进细胞骨架结构重组,调节片状伪足与丝状伪足伸延,影响细胞的形体极化,增强细胞运动迁移。p21活化激酶(PAKs)是Rho GTPase的下游效应蛋白,可被活化的Rac1蛋白激活并可通过p21结合域(p21 activated kinase binding domain, PBD)与活化Rac1蛋白结合。为此我们利用RT-PCR方法,以大鼠骨髓间充质干细胞的总RNA为模板,克隆与活化Rac1相结合的PBD基因片段,经基因测序证实成功构建了pGEX-4T-1/PBD原核表达载体,并纯化了GST-PBD融合蛋白,为进一步研究神经干细胞不同分化状态及迁移过程中活化的Rac1表达奠定了基础。
以上结果表明,SCF通过影响C17.2细胞的迁移速率及迁移效率来影响C17.2细胞的定向迁移,PI3K信号通路参与了此过程;此外不同分化状态的NSCs对SCF响应不同。以上结论进一步揭示了NSCs的分化状态与其迁移的内在联系,为解开NSCs分化和迁移机制之谜及临床移植治疗中枢神经系统疾病和损伤提供了实验依据。
Malignant gliomas remain virtually incurable because of its highly invasive nature, despite extensive surgical excision, radiation and chemotherapy. In vitro as well as in vivo studies demonstrate that neural stem cells (NSCs) display a strong tendency to migrate toward gliomas and surround invading tumor cells, thus highlighting the potential use of NSCs as delivery vehicles for therapeutic genes. However, the mechanisms and factors that regulate migration are not well understood. Gliomas release numerous chemokines and growth factors that are capable of stimulating the directed migration of exogenous and endogenous NSCs into the tumor microenvironment. Here, we focus on the effect of stem cell factor (SCF), one of the factors that are present at the injury sites, on the migration of differentiating NSCs.
In this study, we isolated and purified NSCs from the subventricular zone (SVZ) of newborn SD rats and induced these cells to differentiate with 1% fatal calf serum (FCS). These NSCs were characterized by morphology, antigen expression (nestin, GFAP andβ-III-tubulin) and differentiation potential and results showed that the majority of cells are immunopositive for nestin, indicating that they are undifferentiated neural progenitors. After the withdrawal of FGF-2, cells differentiate into GFAP containing astrocytes,β-III-tubulin-positive neurons.
NSCs from SVZ were cultured for 4 days or 5 days, and then changed to the medium with 1% FCS for differentiation. SCF at 5 ng/ml or 25 ng/ml was added to the differentiating cells. The migratory capability of NSCs at different differentiation states was analyzed by time-lapse video analysis. Our results indicated that treatment with SCF at 5 ng/ml didn’t influence the migration distance during the differentiation period of 0~12 h and 36~48 h, but significantly increased it in the phase of the differentiation of 12~36 h. In response to 25 ng/ml of SCF, the migration distance of the differentiating NSCs increased significantly in 0-36 h rather than the later period (36-48 h). In contrast, the forward migration index (FMI) of NSCs was improved by 25 ng/ml SCF through the whole differentiation period. These results suggest a close relationship between the migration behavior and the differentiation states of NSCs.
Then we investigated SCF-induced migration of C17.2 cells using Boyden chamber and Dunn chamber. Results of Boyden Chamber showed that cells of 24-h differentiation displayed the strongest tropism toward SCF compared with undifferentiated C17.2 cells. After 24 h of differentiation, the migratory responsiveness decreased over time. On the 7th day, less C17.2 cells migrated to SCF than did normal cells that were at an undifferentiated state. The Dunn Chamber results indicated both the migration speed and the forward migration index (FMI) of cells exposed to SCF were significantly greater than those of cells exposed to a uniform concentration of SCF. Cells displayed a directed migratory behavior towards the source of SCF, while they migrated randomly under conditions of uniform SCF distribution. The addition of LY294002, a specific inhibitor of PI3K, significantly altered the pattern of migration of C17.2 cells in response to SCF gradient. The migration speed was significantly decreased compared with untreated cells, while cells remained their directional response to the SCF gradient. These results illustrate that SCF induces the directional migration of C17.2 cells via the increase in the migration efficiency and the migration speed of these cells through activation of PI3K/Akt signaling pathway.
Rac1 is a molecular switch that has an inactive GDP-bound and an active GTP-bound state. After activation, Rac1 can participate in the formation of actin stress and adhesion plaque, promote the reform of cytoskeleton, regulate the extension of lamellipodia and filopodia, influence the polarization of cell, and enhance cell migration. p21-activated kinases (PAKs) are the downstream effector proteins of Rho GTPase. Binding of Rac-GTP leads to PAK autophosphorylation and activation of the ability to phosphorylate exogenous substrates on serine and/or threonine residues. Rac activates PAK through binding to the p21-binding domain (PBD). The gene fragment of PBD was amplified by RT-PCR and cloned into the pGEX-4T-1 prokaryotic expression vector, DNA sequencing confirmed that the expression vector of pGEX-4T-1/ PBD was constructed successfully and fusion protein was expressed effectively in Escherichia coli, with about 95 % of the GST-PBD fusion protein. This study lays the basis for the research on the relationship between the Rac1 activity and the differentiation states of NSCs.
Taken together, these results illustrate that SCF induces the directional migration of NSCs via the increase in the migration efficiency and the migration speed of these cells through activation of PI3K/Akt, contributing to better understanding of the migration and differentiation mechanisms of NSCs, and thus helping design the therapeutic strategies to treat central nervous system (CNS) diseases.
本研究首先从新生远交群(Sprague Dawley, SD)大鼠侧脑室外侧壁的脑室下区(the subventricular zone, SVZ)中分离并纯化出NSCs,用含1%胎牛血清的H-DMEM进行诱导分化,并通过对细胞形态、生长特性及特异性抗原(nestin、GFAP和β-III-tubulin)表达对细胞进行了鉴定。结果表明,SVZ区域来源的NSCs呈nestin阳性,更换分化诱导液后能分化成神经元(β-III-tubulin+)和星形胶质细胞(GFAP+)。
随后选取生长第4～5天的NSCs,更换含不同浓度干细胞因子(stem cell factor, SCF)的分化培养基对NSCs进行处理。通过延时动态视频(time-lapse video)跟踪观察NSCs分化0-48 h的不同阶段下对SCF的刺激做出应答时其迁移行为发生了哪些变化。含不同浓度SCF的分化诱导液对NSCs处理后结果表明,与对照组相比,5 ng/ml的SCF未能对分化0-12 h及36-48 h内的NSCs的迁移距离产生影响,但显著提高了分化12-36 h内NSCs的迁移距离。而25 ng/ml的SCF在分化0-36 h内的迁移距离显著高于对照组但未能对分化36-48 h内NSCs的迁移距离产生影响,并且仅在分化0-12 h内NSCs的迁移距离显著高于5 ng/ml的SCF。与此同时,与对照组相比,5 ng/ml的SCF显著提高了分化0-36 h内NSCs的迁移效率(forward migration index, FMI),但未能影响分化36-48 h内的FMI。而25 ng/ml的SCF在分化0-48 h内的迁移效率显著高于对照组,而且在分化的36-48 h内显著高于5 ng/ml的SCF实验组,但在分化0-36 h内两实验组无显著差异。这些现象表明,NSCs的迁移行为与其所处的分化状态有着紧密的内在联系。
为了进一步验证前期的实验结果并为后期的体内等机理性研究做准备,我们选择了C17.2神经干细胞系,运用Boyden chamber及Dunn chamber来研究SCF诱导C17.2神经干细胞的趋化性迁移。Boyden chamber结果显示,下室加入SCF后迁移至膜下方的C17.2细胞数显著多于对照组。在C17.2分化24 h时其对SCF的应答最强,定向迁移的细胞数要明显多于未分化状态。而随着分化进程的深入,其迁移能力逐渐降低,到第7 d时已显著低于未分化状态。Dunn chamber结果显示,仅在外槽加入SCF的C17.2细胞迁移速率及迁移效率显著高于内外槽均加入SCF的细胞,单个细胞迁移轨迹分析表明仅在外槽加入SCF后细胞朝着浓度梯度方向迁移而内外槽均加入SCF后细胞的迁移则无规律。用LY294002阻断PI3K通路后,C17.2细胞向SCF迁移的速率显著降低,但并未影响其定向迁移能力。这些结果表明,SCF通过影响C17.2细胞的迁移速率及迁移效率来影响C17.2细胞的定向迁移,PI3K信号通路参与了此过程;而且不同分化阶段的C17.2细胞对SCF的响应能力不同,为进一步了解神经干细胞定向追踪胶质瘤提供了理论依据。
Rac亚家族中Rac1的功能一直以来都是研究的热点。Rac1蛋白具有活性Rac1-GTP和非活性Rac1-GDP两种状态,当Rac1被激活后,可参与肌动蛋白应力纤维和粘附斑形成,促进细胞骨架结构重组,调节片状伪足与丝状伪足伸延,影响细胞的形体极化,增强细胞运动迁移。p21活化激酶(PAKs)是Rho GTPase的下游效应蛋白,可被活化的Rac1蛋白激活并可通过p21结合域(p21 activated kinase binding domain, PBD)与活化Rac1蛋白结合。为此我们利用RT-PCR方法,以大鼠骨髓间充质干细胞的总RNA为模板,克隆与活化Rac1相结合的PBD基因片段,经基因测序证实成功构建了pGEX-4T-1/PBD原核表达载体,并纯化了GST-PBD融合蛋白,为进一步研究神经干细胞不同分化状态及迁移过程中活化的Rac1表达奠定了基础。
以上结果表明,SCF通过影响C17.2细胞的迁移速率及迁移效率来影响C17.2细胞的定向迁移,PI3K信号通路参与了此过程;此外不同分化状态的NSCs对SCF响应不同。以上结论进一步揭示了NSCs的分化状态与其迁移的内在联系,为解开NSCs分化和迁移机制之谜及临床移植治疗中枢神经系统疾病和损伤提供了实验依据。
Malignant gliomas remain virtually incurable because of its highly invasive nature, despite extensive surgical excision, radiation and chemotherapy. In vitro as well as in vivo studies demonstrate that neural stem cells (NSCs) display a strong tendency to migrate toward gliomas and surround invading tumor cells, thus highlighting the potential use of NSCs as delivery vehicles for therapeutic genes. However, the mechanisms and factors that regulate migration are not well understood. Gliomas release numerous chemokines and growth factors that are capable of stimulating the directed migration of exogenous and endogenous NSCs into the tumor microenvironment. Here, we focus on the effect of stem cell factor (SCF), one of the factors that are present at the injury sites, on the migration of differentiating NSCs.
In this study, we isolated and purified NSCs from the subventricular zone (SVZ) of newborn SD rats and induced these cells to differentiate with 1% fatal calf serum (FCS). These NSCs were characterized by morphology, antigen expression (nestin, GFAP andβ-III-tubulin) and differentiation potential and results showed that the majority of cells are immunopositive for nestin, indicating that they are undifferentiated neural progenitors. After the withdrawal of FGF-2, cells differentiate into GFAP containing astrocytes,β-III-tubulin-positive neurons.
NSCs from SVZ were cultured for 4 days or 5 days, and then changed to the medium with 1% FCS for differentiation. SCF at 5 ng/ml or 25 ng/ml was added to the differentiating cells. The migratory capability of NSCs at different differentiation states was analyzed by time-lapse video analysis. Our results indicated that treatment with SCF at 5 ng/ml didn’t influence the migration distance during the differentiation period of 0~12 h and 36~48 h, but significantly increased it in the phase of the differentiation of 12~36 h. In response to 25 ng/ml of SCF, the migration distance of the differentiating NSCs increased significantly in 0-36 h rather than the later period (36-48 h). In contrast, the forward migration index (FMI) of NSCs was improved by 25 ng/ml SCF through the whole differentiation period. These results suggest a close relationship between the migration behavior and the differentiation states of NSCs.
Then we investigated SCF-induced migration of C17.2 cells using Boyden chamber and Dunn chamber. Results of Boyden Chamber showed that cells of 24-h differentiation displayed the strongest tropism toward SCF compared with undifferentiated C17.2 cells. After 24 h of differentiation, the migratory responsiveness decreased over time. On the 7th day, less C17.2 cells migrated to SCF than did normal cells that were at an undifferentiated state. The Dunn Chamber results indicated both the migration speed and the forward migration index (FMI) of cells exposed to SCF were significantly greater than those of cells exposed to a uniform concentration of SCF. Cells displayed a directed migratory behavior towards the source of SCF, while they migrated randomly under conditions of uniform SCF distribution. The addition of LY294002, a specific inhibitor of PI3K, significantly altered the pattern of migration of C17.2 cells in response to SCF gradient. The migration speed was significantly decreased compared with untreated cells, while cells remained their directional response to the SCF gradient. These results illustrate that SCF induces the directional migration of C17.2 cells via the increase in the migration efficiency and the migration speed of these cells through activation of PI3K/Akt signaling pathway.
Rac1 is a molecular switch that has an inactive GDP-bound and an active GTP-bound state. After activation, Rac1 can participate in the formation of actin stress and adhesion plaque, promote the reform of cytoskeleton, regulate the extension of lamellipodia and filopodia, influence the polarization of cell, and enhance cell migration. p21-activated kinases (PAKs) are the downstream effector proteins of Rho GTPase. Binding of Rac-GTP leads to PAK autophosphorylation and activation of the ability to phosphorylate exogenous substrates on serine and/or threonine residues. Rac activates PAK through binding to the p21-binding domain (PBD). The gene fragment of PBD was amplified by RT-PCR and cloned into the pGEX-4T-1 prokaryotic expression vector, DNA sequencing confirmed that the expression vector of pGEX-4T-1/ PBD was constructed successfully and fusion protein was expressed effectively in Escherichia coli, with about 95 % of the GST-PBD fusion protein. This study lays the basis for the research on the relationship between the Rac1 activity and the differentiation states of NSCs.
Taken together, these results illustrate that SCF induces the directional migration of NSCs via the increase in the migration efficiency and the migration speed of these cells through activation of PI3K/Akt, contributing to better understanding of the migration and differentiation mechanisms of NSCs, and thus helping design the therapeutic strategies to treat central nervous system (CNS) diseases.
引文
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1. Gage, F.H., Mammalian neural stem cells. Science, 2000. 287(5457): 1433-8.
2. Luskin, M.B., Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron, 1993. 11(1): 173-89.
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