血管内皮生长因子在人胚胎干细胞神经分化过程中的作用及相关机制研究
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摘要
近年来，人胚胎干细胞(human embryonic stem cells，hESCs)向神经细胞诱导分化的成功，为各种难治性神经系统疾病细胞移植治疗提供了理想的载体。从胚胎干细胞诱导分化为特异的神经元或胶质细胞的关键步骤是神经干细胞(neural stem cells，NSCs)的生成。目前采用的hESCs分化为NSCs的诱导方法大致可分为三种：一是经拟胚体(embryonic bodies，EBs)诱导法。通过模仿胚胎内生成神经外胚层的环境来产生神经干细胞，是应用最广泛的诱导方法。但是该法周期长，所需hESCs细胞量大，操作技术含量较高。二是与具有特殊诱导能力的基质细胞共培养法。不过基质细胞所提供因子的具体作用未被阐述，是否对神经细胞有后续作用尚需进一步观察，一定程度上阻碍其应用；三是用特定的诱导因子使胚胎干细胞直接定向分化法。研究发现去除细胞内各种抑制神经分化的信号传导和细胞间相互抑制作用时，未分化的ESCs会自发向神经细胞分化，基于此产生了直接分化法。该法诱导hESCs生成NSCs已有报道，但尚未形成统一有效的诱导方法。对脊椎动物成体内神经发生的研究表明，内皮细胞通过产生血管微环境(vascular niche)，促进成体神经干细胞的增殖。在体外，内皮细胞也可以诱导大鼠神经干细胞转化成神经元。血管内皮生长因子(vascular endothelial growth factor，VEGF)是内皮细胞分泌的主要因子，在这些体内外过程中发挥关键作用。VEGF通过VEGFR2．对海马等脑组织内神经发生区的神经干细胞发挥促生长、存活和趋化的作用。研究发现干细胞本身也可以产生分化调控信号来调节自身的增殖分化。诸多研究初步揭示了Notch信号转导通路在维持神经干细胞多能性、调节神经元和胶质细胞分化中有重要作用。此外，研究表明丝裂原活化蛋白激酶(mitogen activated protein kinase，MAPK)信号转导途径在中枢神经系统广泛表达，各种细胞外刺激信号均可通过这一通路影响突触传递，神经元的重塑和生存等。本研究对经EB法与直接分化法诱导hESCs生成NSCs进行比较，以探索适合临床应用的经济高效的诱导方法。随后将探讨在体外hESCs神经分化中VEGF是否发挥作用，该作用与Notch和p38 MAPK信号转导通路是否相关，以更深入的研究神经发生过程，明确神经细胞分化中的决定因素和其中的各种相互关系。
第一部分人胚胎干细胞体外分化为神经干细胞诱导方法的研究
目的探讨适合临床应用的经济高效的人胚胎干细胞分化为神经干细胞的方法。
方法人胚胎干细胞生长成熟后，将其脱离饲养层，分离消化为单细胞，以1×10~5的细胞密度置于培养皿(板)中，用直接分化培养基培养，诱导细胞向神经干细胞分化。
结果用直接分化培养基培养脱离饲养层的hESCs，约14～16天生成nestin阳性的NSCs。神经干细胞继续分化，可以得到不同数量的神经元和胶质细胞，MAP2、GFAP分别阳性。
结论在体外人胚胎干细胞不经EB，可以直接定向分化为神经干细胞。该方法与传统的经EB法相比，周期短、操作过程简单、成本低，可用于神经系统疾病移植治疗研究中hESCs向NSCs分化的大批量诱导。
第二部分血管内皮生长因子在体外hESCs诱导分化为神经细胞中的作用研究
目的观察血管内皮生长因子在体外hESCs分化为神经细胞过程中是否发挥作用。
方法人胚胎干细胞经拟胚体向神经细胞分化，分别给予VEGF(10ng／mL)和VEGF(10ng／mL)+VEGFR2／Fc嵌合体(10ng／mL)添加入神经细胞分化的各个阶段，通过RT-PCR、免疫荧光法检测各阶段细胞标志物，计算并用流式细胞仪检测各组神经干细胞Nestin的阳性率。
结果RT-PCR检测到各阶段细胞标记物表达，在人神经干细胞检测到VEGFR2表达；免疫荧光法检测，VEGF作用组产生神经干细胞、分化为神经元的比率明显高于常规经EB诱导组和VEGF+VEGFR2／Fc嵌合体作用组，常规诱导组和VEGF+VEGFR2／Fc嵌合体作用组之间各阶段阳性细胞率无明显差异。
结论人神经干细胞表达VEGFR2；在体外人胚胎干细胞向神经细胞的分化过程中，小剂量(10ng／mL)血管内皮生长因子通过血管内皮生长因子受体2，促进神经干细胞增殖及向神经元分化。
第三部分人胚胎干细胞定向分化为神经细胞中VEGF作用机制的初步研究
目的研究血管内皮生长因子在体外hESCs分化为神经元过程中的作用机制。
方法人胚胎干细胞经拟胚体向神经元分化，在VEGF(10ng／mL)作用之前，分别在各阶段细胞中给予γ-分泌酶抑制剂和p38 MAPK抑制剂作用1h，免疫荧光法计算各阶段细胞阳性率，并与常规诱导组和单独VEGF作用组相比较，半定量RT-PCR分析各组细胞Notch信号靶基因Hes1mRNA和p38αmRNA表达。
结果hESCs经由EB诱导分化为神经干细胞过程中，γ-分泌酶抑制剂预处理组与常规诱导组神经干细胞的阳性率无明显差异，p38 MAPK抑制剂预处理组的神经干细胞比例与VEGF组无明显差异；RT-PCR检测发现，VEGF作用组Hes1mRNA的表达强于γ-分泌酶抑制剂预处理组和常规诱导组，MTT检测VEGF作用组细胞增殖活性最强。在NSCs进一步分化为神经元中，γ-分泌酶抑制剂预处理组和VEGF作用组的神经元阳性率无明显差异；p38 MAPK抑制剂预处理组与常规诱导组的神经元比例无明显差异，RT-PCR分析显示，VEGF作用组p38αmRNA表达高于p38 MAPK抑制剂预处理组和常规诱导组。
结论VEGF通过激活Notch信号转导通路，促进人胚胎干细胞经EB分化为神经干细胞。Notch信号抑制剂可以拮抗这一过程中VEGF的作用，而p38 MAPK与这一过程无明显相关。在人神经干细胞定向分化为神经元中，VEGF经由p38 MAPK途径，促进神经干细胞更多的分化为神经元。p38 MAPK抑制剂可以阻断VEGF的这一作用，Notch信号通路对这一过程不产生影响。
In recent years,the differentiation from human embryonic stem cells (hESCs) toneuronal cells provides an ideal vector for cell transplantation therapy of neurodegenerativediseases.The generation of neural stem cells (NSCs) is a key step in the induction fromembryonic stem cells to specific neurons or glial cells.There are broadly three kinds ofmethods used in hESCs differentiated into NSCs:First is the method with embryonic body(EB) culture period.It is the most widely used one.However,this method is too long andrequires a large amount of hESCs.Second one is co-culture with the special-induced stromalcells.But it has not been explained whether the factors secreted from stromal cells have othereffect on the neural cells.So this hinders the application to some extent.Third is the methodof using specific factors to direct differentiate embryonic stem cells.Studies found that whena variety of signal transduction in cells and cell interaction were removal,ESCsspontaneously differentiated into the neuronal cells.The inductions of NSCs from hESCsusing this method have been reported,but there does not form a unified and effective method.Researches of neurogenesis in the vertebrate have shown that vascular endothelial cellspromote adult neural stem cell proliferation through vascular niche In vitro,endothelial cellscan induce rat neural stem cells into neurons.Vascular endothelial growth factor (VEGF)secreted by endothelial cells,play an essential role in these process in vitro and in vivo.In the hippocampus,VEGF promot neural stem cells growth and survival through VEGFR2.Studiesfound that stern cells could produce signals to regulate the proliferation and differentiation ofthemselves.Preliminary studies have revealed Notch signal transduction pathway has animportant effect in the proliferation of multipotent neural stem cells.In addition,mitogenactivated protein kinase (MAPK) signal transduction pathway is widely expressed in thecentral nervous system.A variety of extracellular signals through this pathway may affect thesynaptic transmission and neurons survival.In this study,we use the EB method and thedirect differentiation to induce human embryonic stem cells into neural stem cells in order toexplore the suitable induction method.Then we will explore whether VEGF play a role in theneural differentiation of human embryonic stem cells in vitro and the effect of VEGF isrelated to Notch and p38 MAPK signal transduction pathway or not.
PartⅠDifferentiation of Human Embryonic Stem Cells intoNeural Stem Cells in vitro
Objective To find an efficient and economical method to differentiate humanembryonic stem cells into neural stem cells in vitro
Methods hESCs were matured and free from the feeder layer,digested for thesingle-cell.The cells with 1×10~5 density cultured in dish and induced by Noggin and ITSFndirectly without EB culturing.
Results By the direct differentiation,Nestin-positive NSCs were generated after 14～16days.The neural stem cells could be differentiated into neurons and glial cells.MAP2 andGFAP were detected after the differentiation of neural stem cells.
Conclusion hESCs can successfully differentiate into neural stem cells without EBculture period in vitro.This method has the better effect than the traditional one and will beused for the cell transplantation in the research of nervous system diseases.
PartⅡEffect of VEGF on Neural Differentiation ofHuman Embryonic Stem Cells in vitro
Objective To observe the effect of VEGF on neural differentiation of human embryonicstem cells in vitro
Methods After embryonic body formation,hESCs were differentiated into neuronalcells.10ng/mL VEGF or 10ng/mL VEGF + 10ng/mLVEGFR2/Fc were added at every stageof differentiation.The markers of every stage were detected through RT-PCR.Nestin andMAP2 expressing cells were detected via immunofluorescence method.The percentages ofthe imunostaining positive cells were determined by flow cytometer (FCM).
Results The markers of different stages were detected by RT-PCR.The expression ofVEGFR2 was detected in human neural stem cells using RT-PCR.The percentage of Nestinand MAP2 positive cells in VEGF treated group were much higher than that in routineinduction group and VEGF+VEGFR2/Fc treated group.There was no difference betweenroutine induction group and VEGF+VEGFR2/Fc treated group.
Conclusion hNSCs express VEGFR2.Low dose (10ng/mL) of VEGF,via VEGFR2,stimulates the proliferation of NSCs and the neuronal cells differentiation from humanembryonic stem cells in vitro.
PartⅢThe Mechanism of VEGF on Neural Differentiation ofHuman Embryonic Stem in vitro
Objective To study the mechanism of VEGF on the neural differentiation of hESCs invitro
Methods hESCs were cultured and differentiated into neurons through the embryonic body.Before the VEGF (10ng/mL) was added,γ-secretase inhibitor and p38 MAPK inhibitorwere given at every stage of induction for 1h.The markers of every stage were detected andthe percentages of the imunostaining positive cells were counted throughimmunofluorescence.The expressions of HeslmRNA and p38αmRNA in each group weredetected by RT-PCR.
Results The percentage of Nestin in theγ-secretase inhibitors pretreatment group wassimilar with the conventional group.The applications of p38 MAPK inhibitor produced thesimilar number of neural stem cells with the VEGF group;RT-PCR revealed that theexpression of HeslmRNA in the VEGF-treated group was higher thanγ-secretase inhibitorpreconditioning group and the conventional group.After the differentiation of NSCs intoneurons,the neurons generated fromγ-secretase inhibitors group and the VEGF-treated grouphad no significant difference,while the neurons of p38 MAPK inhibitor pretreatment groupand conventional induction group were similar.RT-PCR analysis showed that the expressionof p38αmRNA in the VEGF-treated group was higher than p38 MAPK inhibitorpreconditioning group and the conventional group.
Conclusion Through the activation of Notch signal transduction pathway,VEGF play arole in promoting human embryonic stem cell differentiated into neural stem cells.Theinhibitor of Notch signaling can antagonize the effect of VEGF in this process.In thedifferentiation of human neural stem cells into neurons,VEGF can promote neural stem cellsto differentiate into more neurons via p38MAPK way.p38 MAPK inhibitors can block therole of VEGF in this process.
第一部分人胚胎干细胞体外分化为神经干细胞诱导方法的研究
目的探讨适合临床应用的经济高效的人胚胎干细胞分化为神经干细胞的方法。
方法人胚胎干细胞生长成熟后，将其脱离饲养层，分离消化为单细胞，以1×10~5的细胞密度置于培养皿(板)中，用直接分化培养基培养，诱导细胞向神经干细胞分化。
结果用直接分化培养基培养脱离饲养层的hESCs，约14～16天生成nestin阳性的NSCs。神经干细胞继续分化，可以得到不同数量的神经元和胶质细胞，MAP2、GFAP分别阳性。
结论在体外人胚胎干细胞不经EB，可以直接定向分化为神经干细胞。该方法与传统的经EB法相比，周期短、操作过程简单、成本低，可用于神经系统疾病移植治疗研究中hESCs向NSCs分化的大批量诱导。
第二部分血管内皮生长因子在体外hESCs诱导分化为神经细胞中的作用研究
目的观察血管内皮生长因子在体外hESCs分化为神经细胞过程中是否发挥作用。
方法人胚胎干细胞经拟胚体向神经细胞分化，分别给予VEGF(10ng／mL)和VEGF(10ng／mL)+VEGFR2／Fc嵌合体(10ng／mL)添加入神经细胞分化的各个阶段，通过RT-PCR、免疫荧光法检测各阶段细胞标志物，计算并用流式细胞仪检测各组神经干细胞Nestin的阳性率。
结果RT-PCR检测到各阶段细胞标记物表达，在人神经干细胞检测到VEGFR2表达；免疫荧光法检测，VEGF作用组产生神经干细胞、分化为神经元的比率明显高于常规经EB诱导组和VEGF+VEGFR2／Fc嵌合体作用组，常规诱导组和VEGF+VEGFR2／Fc嵌合体作用组之间各阶段阳性细胞率无明显差异。
结论人神经干细胞表达VEGFR2；在体外人胚胎干细胞向神经细胞的分化过程中，小剂量(10ng／mL)血管内皮生长因子通过血管内皮生长因子受体2，促进神经干细胞增殖及向神经元分化。
第三部分人胚胎干细胞定向分化为神经细胞中VEGF作用机制的初步研究
目的研究血管内皮生长因子在体外hESCs分化为神经元过程中的作用机制。
方法人胚胎干细胞经拟胚体向神经元分化，在VEGF(10ng／mL)作用之前，分别在各阶段细胞中给予γ-分泌酶抑制剂和p38 MAPK抑制剂作用1h，免疫荧光法计算各阶段细胞阳性率，并与常规诱导组和单独VEGF作用组相比较，半定量RT-PCR分析各组细胞Notch信号靶基因Hes1mRNA和p38αmRNA表达。
结果hESCs经由EB诱导分化为神经干细胞过程中，γ-分泌酶抑制剂预处理组与常规诱导组神经干细胞的阳性率无明显差异，p38 MAPK抑制剂预处理组的神经干细胞比例与VEGF组无明显差异；RT-PCR检测发现，VEGF作用组Hes1mRNA的表达强于γ-分泌酶抑制剂预处理组和常规诱导组，MTT检测VEGF作用组细胞增殖活性最强。在NSCs进一步分化为神经元中，γ-分泌酶抑制剂预处理组和VEGF作用组的神经元阳性率无明显差异；p38 MAPK抑制剂预处理组与常规诱导组的神经元比例无明显差异，RT-PCR分析显示，VEGF作用组p38αmRNA表达高于p38 MAPK抑制剂预处理组和常规诱导组。
结论VEGF通过激活Notch信号转导通路，促进人胚胎干细胞经EB分化为神经干细胞。Notch信号抑制剂可以拮抗这一过程中VEGF的作用，而p38 MAPK与这一过程无明显相关。在人神经干细胞定向分化为神经元中，VEGF经由p38 MAPK途径，促进神经干细胞更多的分化为神经元。p38 MAPK抑制剂可以阻断VEGF的这一作用，Notch信号通路对这一过程不产生影响。
In recent years,the differentiation from human embryonic stem cells (hESCs) toneuronal cells provides an ideal vector for cell transplantation therapy of neurodegenerativediseases.The generation of neural stem cells (NSCs) is a key step in the induction fromembryonic stem cells to specific neurons or glial cells.There are broadly three kinds ofmethods used in hESCs differentiated into NSCs:First is the method with embryonic body(EB) culture period.It is the most widely used one.However,this method is too long andrequires a large amount of hESCs.Second one is co-culture with the special-induced stromalcells.But it has not been explained whether the factors secreted from stromal cells have othereffect on the neural cells.So this hinders the application to some extent.Third is the methodof using specific factors to direct differentiate embryonic stem cells.Studies found that whena variety of signal transduction in cells and cell interaction were removal,ESCsspontaneously differentiated into the neuronal cells.The inductions of NSCs from hESCsusing this method have been reported,but there does not form a unified and effective method.Researches of neurogenesis in the vertebrate have shown that vascular endothelial cellspromote adult neural stem cell proliferation through vascular niche In vitro,endothelial cellscan induce rat neural stem cells into neurons.Vascular endothelial growth factor (VEGF)secreted by endothelial cells,play an essential role in these process in vitro and in vivo.In the hippocampus,VEGF promot neural stem cells growth and survival through VEGFR2.Studiesfound that stern cells could produce signals to regulate the proliferation and differentiation ofthemselves.Preliminary studies have revealed Notch signal transduction pathway has animportant effect in the proliferation of multipotent neural stem cells.In addition,mitogenactivated protein kinase (MAPK) signal transduction pathway is widely expressed in thecentral nervous system.A variety of extracellular signals through this pathway may affect thesynaptic transmission and neurons survival.In this study,we use the EB method and thedirect differentiation to induce human embryonic stem cells into neural stem cells in order toexplore the suitable induction method.Then we will explore whether VEGF play a role in theneural differentiation of human embryonic stem cells in vitro and the effect of VEGF isrelated to Notch and p38 MAPK signal transduction pathway or not.
PartⅠDifferentiation of Human Embryonic Stem Cells intoNeural Stem Cells in vitro
Objective To find an efficient and economical method to differentiate humanembryonic stem cells into neural stem cells in vitro
Methods hESCs were matured and free from the feeder layer,digested for thesingle-cell.The cells with 1×10~5 density cultured in dish and induced by Noggin and ITSFndirectly without EB culturing.
Results By the direct differentiation,Nestin-positive NSCs were generated after 14～16days.The neural stem cells could be differentiated into neurons and glial cells.MAP2 andGFAP were detected after the differentiation of neural stem cells.
Conclusion hESCs can successfully differentiate into neural stem cells without EBculture period in vitro.This method has the better effect than the traditional one and will beused for the cell transplantation in the research of nervous system diseases.
PartⅡEffect of VEGF on Neural Differentiation ofHuman Embryonic Stem Cells in vitro
Objective To observe the effect of VEGF on neural differentiation of human embryonicstem cells in vitro
Methods After embryonic body formation,hESCs were differentiated into neuronalcells.10ng/mL VEGF or 10ng/mL VEGF + 10ng/mLVEGFR2/Fc were added at every stageof differentiation.The markers of every stage were detected through RT-PCR.Nestin andMAP2 expressing cells were detected via immunofluorescence method.The percentages ofthe imunostaining positive cells were determined by flow cytometer (FCM).
Results The markers of different stages were detected by RT-PCR.The expression ofVEGFR2 was detected in human neural stem cells using RT-PCR.The percentage of Nestinand MAP2 positive cells in VEGF treated group were much higher than that in routineinduction group and VEGF+VEGFR2/Fc treated group.There was no difference betweenroutine induction group and VEGF+VEGFR2/Fc treated group.
Conclusion hNSCs express VEGFR2.Low dose (10ng/mL) of VEGF,via VEGFR2,stimulates the proliferation of NSCs and the neuronal cells differentiation from humanembryonic stem cells in vitro.
PartⅢThe Mechanism of VEGF on Neural Differentiation ofHuman Embryonic Stem in vitro
Objective To study the mechanism of VEGF on the neural differentiation of hESCs invitro
Methods hESCs were cultured and differentiated into neurons through the embryonic body.Before the VEGF (10ng/mL) was added,γ-secretase inhibitor and p38 MAPK inhibitorwere given at every stage of induction for 1h.The markers of every stage were detected andthe percentages of the imunostaining positive cells were counted throughimmunofluorescence.The expressions of HeslmRNA and p38αmRNA in each group weredetected by RT-PCR.
Results The percentage of Nestin in theγ-secretase inhibitors pretreatment group wassimilar with the conventional group.The applications of p38 MAPK inhibitor produced thesimilar number of neural stem cells with the VEGF group;RT-PCR revealed that theexpression of HeslmRNA in the VEGF-treated group was higher thanγ-secretase inhibitorpreconditioning group and the conventional group.After the differentiation of NSCs intoneurons,the neurons generated fromγ-secretase inhibitors group and the VEGF-treated grouphad no significant difference,while the neurons of p38 MAPK inhibitor pretreatment groupand conventional induction group were similar.RT-PCR analysis showed that the expressionof p38αmRNA in the VEGF-treated group was higher than p38 MAPK inhibitorpreconditioning group and the conventional group.
Conclusion Through the activation of Notch signal transduction pathway,VEGF play arole in promoting human embryonic stem cell differentiated into neural stem cells.Theinhibitor of Notch signaling can antagonize the effect of VEGF in this process.In thedifferentiation of human neural stem cells into neurons,VEGF can promote neural stem cellsto differentiate into more neurons via p38MAPK way.p38 MAPK inhibitors can block therole of VEGF in this process.
引文
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