BDNF基因转染骨髓间充质干细胞向神经元样细胞分化及对耳蜗螺旋神经元保护作用初步研究
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摘要
第一章人脑源性神经营养因子基因真核表达载体的构建及表达
目的神经营养因子(neurotrophic factors,NTFs)在神经系统的生长发育、功能维持过程中发挥重大影响。近年来神经营养因子家族一些成员纷纷被克隆并应用于神经系统疾病的防治,取得了可喜进展。脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)作为神经营养因子家族成员,与外周听觉系统有着密切关系,不仅对耳蜗前庭神经元的发育成熟、增殖分化起重要作用,而且对损伤后神经元的修复、存活与功能重塑也影响深远。在此基础上,本研究对人脑源性神经营养因子(human BDNF,hBDNF)进行克隆,构建hBDNF真核表达载体pcDNA3.1(-)-BDNF,并用该载体转染人胚胎肾293细胞(human embryo kidney 293 cells,HEK293)后检测BDNF的表达,为耳聋防治的进一步研究提供了基因来源。
方法RT-PCR扩增人胚胎脑组织hBDNF基因片段,将基因片段与pcDNA3.1(-)质粒连接制成重组质粒。转化、筛选及扩增重组质粒,用EcoRⅠ和BamHⅠ酶切分析鉴定BDNF是否插入重组质粒。小量提取重组质粒后进行测序分析,将酶切检测和测序正确的pcDNA 3.1(-)-BDNF重组质粒用QIAGEN-TIP100大量提取。重组质粒转染HEK293细胞,Western Blot法检测细胞中BDNF的表达。
结果应用RT-PCR技术克隆出hBDNF基因。将hBDNF片段与pcDNA3.1(-)连接,成功构建重组质粒pcDNA3.1(-)-BDNF。酶切鉴定、DNA序列测定结果证实插入片段为hBDNF基因全长片段。Western Blot法检测到转染pcDNA3.1(-)-BDNF的HEK293细胞中有BDNF的表达。
结论成功构建了含hBDNF基因的真核表达载体:pcDNA3.1(-)-hBDNF,为开展基因治疗提供了重要的基因来源。
第二章脑源性神经营养因子基因电穿孔法转染骨髓间充质干细胞体外诱导分化为神经元样细胞观察
目的探讨骨髓间充质干细胞(bone-marrow mesenchymal stemcells,BMSCs)在转染人脑源性神经营养因子(BDNF)基因后在体外分化为神经元样细胞的功能。
方法人BDNF基因克隆并构建其真核表达载体。取5只豚鼠的骨髓,分离培养贴壁细胞,观察其形态。CD34、CD44、CD45抗体流式细胞术鉴定所培养的细胞为BMSCs。将人BDNF基因电穿孔法转染BMSCs,G418筛选后用维甲酸(RA)诱导分化,神经元特异性烯醇化酶(NSE)、巢蛋白(Nestin)和胶质纤维酸性蛋白(GFAP)抗体免疫细胞化学对分化细胞进行鉴定。
结果分离培养的细胞具有典型的BMSCs形态和标志,人BDNF基因电穿孔法转染BMSCs的转染率约为25%,转染诱导后的细胞在外观上类似神经细胞,表达NSE、Nestin和GFAP。
结论BDNF基因转染的BMSCs在体外能分化为神经元样细胞,电穿孔法能提高转染率,RA有促诱导作用。
第三章脑源性神经营养因子基因转染骨髓间充质干细胞耳蜗内移植初步观察
目的探讨脑源性神经营养因子基因转染的骨髓间充质干细胞在受损耳蜗内的分化及保护功能。
方法将转染了脑源性神经营养因子基因,并在体外诱导分化的骨髓间充质干细胞(BDNF-BMSCs)标记后,通过鼓阶注射植入阿米卡星致聋的豚鼠耳蜗内。并设耳蜗单纯注射人工外淋巴液、BMSCs、BDNF基因作为对照组。分别在注射后1W、2W、4W取耳蜗组织石蜡包埋切片。HE染色观察耳蜗组织病理学变化,计算SGNs密度;了解BMSCs的分布;NSE、Nestin和GFAP抗体免疫组织化学,观察BMSCs在蜗内的分化和SGNs的存活情况。
结果阿米卡星致聋后豚鼠耳蜗结构受到损伤,SGNs数减少。诱导分化前后的BMSCs在耳蜗内均能成活并分布到一定的区域。
NSE、Nestin和GFAP免疫化学可见诱导分化后的BMSCs部分细胞阳性染色,而未诱导分化的BMSCs阳性细胞较少。用平均光密度(average optical density,AOD)分析免疫化学结果显示:耳蜗内BDNF-BMSCs在1W、2W时保持了较高的AOD值,和体外比较无明显区别,但在4W时显著下降(P＜0.05);在各时间点,BDNF-BMSCs组AOD值均显著高于BMSCs组(P＜0.01)。
耳蜗内植入BMSCs、BDNF基因、BDNF-BMSCs均可拮抗阿米卡星的耳毒性损伤,其中BDNF-BMSCs保护作用最明显,表现为SGNs形态变化小,密度和NSE免疫化学AOD值高,与对照组比较有显著性差异(P＜0.05)。
结论BDNF基因体外诱导的BMSCs耳蜗内移植后,其分化能力在一定时间内(约2W)保持不变,在4W时下降。耳蜗内移植BDNF-BMSCs比单纯移植BMSCs或BDNF基因具有更好的内耳保护作用。
PartⅠConstruction and expression of recombinant pcDNA3.1(-)-hBDNF plasmid
Objective Neurotrophic factors(NTFs) have great influence on the growth,development and function-maintenance of nervous system. Recent years,some members of NTFs have been cloned and applied into the diseases of nervous system.Much progress has been made in these studies.Brain-derived neurotrophic factor(BDNF),as a member of the family of NTFs,is closely connected with mammalian peripherial auditory system.BDNF not only plays an important role in the regulation of development,maturity,prolifaction and differenation of auditory neurons, but also has strongly ability to remodel the specific function in adulthood and prevent or reduce secondary degeneration after the destruction of auditory neuron.On this condition,the purpose of our study is to make basis for gene engineering production of BDNF and make construction of eukaryotic expression vector:pcDNA3.1(-)-BDNF,and to detect the expression of BDNF after the vector transfects human embryo kidney 293 cells.The source of BDNF gene was provided for the luther study of the prevention and treatment of sensorineural deafness.
Methods Human brain-derived neurotrophic factor gene(hBDNF) was obtained by RT-PCR method,and recombinant pcDNA3.1(-)-hBDNF plasmid was constructed by connecting the gene with pcDNA3.1(-) plasmid.The recombinant plasmid was analyzed and identified by the EcoRⅠand BamHⅠrestriction endonuclease after transformed,screened and amplified.Small amounts of recombinant plasmid was extracted and sequenced,then the correct recombinant pcDNA3.1(-)-BDNF plasmid was massively extracted with QIAGEN-TIP100 kit.HEK293 was transfected by pcDNA3.1(-)-BDNF plasmid,BDNF in the HEK293 was detected with Western Blot.
Results RT-PCR amplification of the hBDNF gene was performed. Recombinant pcDNA3.1(-)-hBDNF plasmid was successfully constructed by connecting the hBDNF gene with pcDNA 3.1(-) plasmid.The human BDNF gene encoding mature peptide was confirmed to be cloned by identified with restriction enzymes and sequenced.BDNF in the HEK293 transfected by pcDNA3.1(-)-BDNF plasmid was confirmed with Western Blot.
Conclusions The recombinant plasmid of pcDNA3.1(-)-hBDNF was constructed successfully,and it could be used in the further experiments for gene therapy.
PartⅡThe observation of bone-marrow mesenchymal stem cells differentiate into neuron-like cells in vitro after transfected by brain- derived neurotrophic factor gene with electroporation
Objective To investigate the differentiation of bone-marrow mesenchymal stem cells(BMSCs) into neuron-like cells in vitro after transfected by human Brain-derived neurotrophic factor(BDNF) gene.
Methods Human BDNF genes were cloned and recombinant pcDNA3.1(-)-BDNF plasmids were constructed.Adherent cells were isolated and cultured from bone marrow of five guinea pigs.The morphology of these cells was observed by microscope and the surface antigen was detected by flowcytometry with CD34,CD44 and CD45 antibody.BDNF gene was transfected to BMSCs with electroporation,the transfected BMSCs were induced by ratinoic acid(RA) after bolted by Geneticin-418(G418),then the differentiated BMSCs were identified by immunocytochemistry of neuron-specificenolase(NSE),Nestin and glial fibrillary acid protien(GFAP)antibody.
Results The culture cells had the typical morphology and surface antigen of BMSCs,the efficiency of human BDNF gene transfected BMSCs with electroporation was about 25%,the transfected cells were similar to nerve cells on appearance and could express NSE,Nestin and GFAP.
Conclusions BMSCs transfected by BDNF gene can differentiate into neuron-like cells in vitro,electroporation can boost the transfection efficiency,RA has the effect to promote induction.
PartⅢPreliminary observation of bone-marrow mesenchymal stem cells transplant into cochlea after transfected by brain-derived neurotrophic factor gene
Objective To investigate the function of differentiation and protection of bone-marrow mesenchymal stem cells(BMSCs) in damaged cochlea after transfected by human brain-derived neurotrophic factor (BDNF) gene.
Methods BMSCs were induced and marked after transfected by hBDNF gene in vitro.These BMSCs(BDNF- BMSCs) were transplanted into tympanic scala of the guinea pigs which were deafened by amikacin(AK).The control groups were designed in which artifical perilymphatic fluid(APF),BMSCs or BDNF gene was injected into cochlea alone.The cochlea was respectively obtained and in paraffin-embedded on the week 1,2 and 4 after injected,and cut in a paramodiolar plane subsequently.Histopathological changes were observed and analyzed by staining with HE,the density of SGNs was calculated,the BMSCs distribution was reviewed,differentiation of BMSCs in vivo and survival of SGNs was detected with immunohistochemistry of NSE,Nestin and GFAP antibody.
Results Construction of the guinea pig cochlea was damaged when amikacin was injected into abdominal cavity,the number of SGNs was decreased.
The result of immunochemistry analyzed with average optical density(AOD) showed:the AOD of the BDNF-BMSCs group in vivo was not obviously different from in vitro on 1W and 2W,but significantly reduced on 4W(P＜0.05),and was significantly higher than the BMSCs group on 1W,2W and 4W(P＜0.01)
BMSCs which were differentiated or not could survive and scatter over some areas in the cochlea.Some induced BMSCs were positive for NSE,Nestin and GFAP,while only a few uninduced BMSCs were positive BMSCs,BDNF gene or BDNF- BMSCs could all rival the ototoxicity of amikacin in the cochlea,the protection taken by BDNF-BMSCs was the most obvious.In the BDNF- BMSCs group it could be confirmed about SGNs that the morphous changed smallest,the density and average optical density for NSE was the highest.The difference was significant compared with the control groups(P＜0.05 )
Conclusions The differentiated ability of BMSCs induced by BDNF gene in vitro is invariable in about two weeks when they are transplanted into the cochlea,but reduces on 4W.The better protection of inner ear is confirmed when BDNF-BMSCs are transplanted into cochlea compared with transplanting BMSCs or BDNF gene alone.
目的神经营养因子(neurotrophic factors,NTFs)在神经系统的生长发育、功能维持过程中发挥重大影响。近年来神经营养因子家族一些成员纷纷被克隆并应用于神经系统疾病的防治,取得了可喜进展。脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)作为神经营养因子家族成员,与外周听觉系统有着密切关系,不仅对耳蜗前庭神经元的发育成熟、增殖分化起重要作用,而且对损伤后神经元的修复、存活与功能重塑也影响深远。在此基础上,本研究对人脑源性神经营养因子(human BDNF,hBDNF)进行克隆,构建hBDNF真核表达载体pcDNA3.1(-)-BDNF,并用该载体转染人胚胎肾293细胞(human embryo kidney 293 cells,HEK293)后检测BDNF的表达,为耳聋防治的进一步研究提供了基因来源。
方法RT-PCR扩增人胚胎脑组织hBDNF基因片段,将基因片段与pcDNA3.1(-)质粒连接制成重组质粒。转化、筛选及扩增重组质粒,用EcoRⅠ和BamHⅠ酶切分析鉴定BDNF是否插入重组质粒。小量提取重组质粒后进行测序分析,将酶切检测和测序正确的pcDNA 3.1(-)-BDNF重组质粒用QIAGEN-TIP100大量提取。重组质粒转染HEK293细胞,Western Blot法检测细胞中BDNF的表达。
结果应用RT-PCR技术克隆出hBDNF基因。将hBDNF片段与pcDNA3.1(-)连接,成功构建重组质粒pcDNA3.1(-)-BDNF。酶切鉴定、DNA序列测定结果证实插入片段为hBDNF基因全长片段。Western Blot法检测到转染pcDNA3.1(-)-BDNF的HEK293细胞中有BDNF的表达。
结论成功构建了含hBDNF基因的真核表达载体:pcDNA3.1(-)-hBDNF,为开展基因治疗提供了重要的基因来源。
第二章脑源性神经营养因子基因电穿孔法转染骨髓间充质干细胞体外诱导分化为神经元样细胞观察
目的探讨骨髓间充质干细胞(bone-marrow mesenchymal stemcells,BMSCs)在转染人脑源性神经营养因子(BDNF)基因后在体外分化为神经元样细胞的功能。
方法人BDNF基因克隆并构建其真核表达载体。取5只豚鼠的骨髓,分离培养贴壁细胞,观察其形态。CD34、CD44、CD45抗体流式细胞术鉴定所培养的细胞为BMSCs。将人BDNF基因电穿孔法转染BMSCs,G418筛选后用维甲酸(RA)诱导分化,神经元特异性烯醇化酶(NSE)、巢蛋白(Nestin)和胶质纤维酸性蛋白(GFAP)抗体免疫细胞化学对分化细胞进行鉴定。
结果分离培养的细胞具有典型的BMSCs形态和标志,人BDNF基因电穿孔法转染BMSCs的转染率约为25%,转染诱导后的细胞在外观上类似神经细胞,表达NSE、Nestin和GFAP。
结论BDNF基因转染的BMSCs在体外能分化为神经元样细胞,电穿孔法能提高转染率,RA有促诱导作用。
第三章脑源性神经营养因子基因转染骨髓间充质干细胞耳蜗内移植初步观察
目的探讨脑源性神经营养因子基因转染的骨髓间充质干细胞在受损耳蜗内的分化及保护功能。
方法将转染了脑源性神经营养因子基因,并在体外诱导分化的骨髓间充质干细胞(BDNF-BMSCs)标记后,通过鼓阶注射植入阿米卡星致聋的豚鼠耳蜗内。并设耳蜗单纯注射人工外淋巴液、BMSCs、BDNF基因作为对照组。分别在注射后1W、2W、4W取耳蜗组织石蜡包埋切片。HE染色观察耳蜗组织病理学变化,计算SGNs密度;了解BMSCs的分布;NSE、Nestin和GFAP抗体免疫组织化学,观察BMSCs在蜗内的分化和SGNs的存活情况。
结果阿米卡星致聋后豚鼠耳蜗结构受到损伤,SGNs数减少。诱导分化前后的BMSCs在耳蜗内均能成活并分布到一定的区域。
NSE、Nestin和GFAP免疫化学可见诱导分化后的BMSCs部分细胞阳性染色,而未诱导分化的BMSCs阳性细胞较少。用平均光密度(average optical density,AOD)分析免疫化学结果显示:耳蜗内BDNF-BMSCs在1W、2W时保持了较高的AOD值,和体外比较无明显区别,但在4W时显著下降(P＜0.05);在各时间点,BDNF-BMSCs组AOD值均显著高于BMSCs组(P＜0.01)。
耳蜗内植入BMSCs、BDNF基因、BDNF-BMSCs均可拮抗阿米卡星的耳毒性损伤,其中BDNF-BMSCs保护作用最明显,表现为SGNs形态变化小,密度和NSE免疫化学AOD值高,与对照组比较有显著性差异(P＜0.05)。
结论BDNF基因体外诱导的BMSCs耳蜗内移植后,其分化能力在一定时间内(约2W)保持不变,在4W时下降。耳蜗内移植BDNF-BMSCs比单纯移植BMSCs或BDNF基因具有更好的内耳保护作用。
PartⅠConstruction and expression of recombinant pcDNA3.1(-)-hBDNF plasmid
Objective Neurotrophic factors(NTFs) have great influence on the growth,development and function-maintenance of nervous system. Recent years,some members of NTFs have been cloned and applied into the diseases of nervous system.Much progress has been made in these studies.Brain-derived neurotrophic factor(BDNF),as a member of the family of NTFs,is closely connected with mammalian peripherial auditory system.BDNF not only plays an important role in the regulation of development,maturity,prolifaction and differenation of auditory neurons, but also has strongly ability to remodel the specific function in adulthood and prevent or reduce secondary degeneration after the destruction of auditory neuron.On this condition,the purpose of our study is to make basis for gene engineering production of BDNF and make construction of eukaryotic expression vector:pcDNA3.1(-)-BDNF,and to detect the expression of BDNF after the vector transfects human embryo kidney 293 cells.The source of BDNF gene was provided for the luther study of the prevention and treatment of sensorineural deafness.
Methods Human brain-derived neurotrophic factor gene(hBDNF) was obtained by RT-PCR method,and recombinant pcDNA3.1(-)-hBDNF plasmid was constructed by connecting the gene with pcDNA3.1(-) plasmid.The recombinant plasmid was analyzed and identified by the EcoRⅠand BamHⅠrestriction endonuclease after transformed,screened and amplified.Small amounts of recombinant plasmid was extracted and sequenced,then the correct recombinant pcDNA3.1(-)-BDNF plasmid was massively extracted with QIAGEN-TIP100 kit.HEK293 was transfected by pcDNA3.1(-)-BDNF plasmid,BDNF in the HEK293 was detected with Western Blot.
Results RT-PCR amplification of the hBDNF gene was performed. Recombinant pcDNA3.1(-)-hBDNF plasmid was successfully constructed by connecting the hBDNF gene with pcDNA 3.1(-) plasmid.The human BDNF gene encoding mature peptide was confirmed to be cloned by identified with restriction enzymes and sequenced.BDNF in the HEK293 transfected by pcDNA3.1(-)-BDNF plasmid was confirmed with Western Blot.
Conclusions The recombinant plasmid of pcDNA3.1(-)-hBDNF was constructed successfully,and it could be used in the further experiments for gene therapy.
PartⅡThe observation of bone-marrow mesenchymal stem cells differentiate into neuron-like cells in vitro after transfected by brain- derived neurotrophic factor gene with electroporation
Objective To investigate the differentiation of bone-marrow mesenchymal stem cells(BMSCs) into neuron-like cells in vitro after transfected by human Brain-derived neurotrophic factor(BDNF) gene.
Methods Human BDNF genes were cloned and recombinant pcDNA3.1(-)-BDNF plasmids were constructed.Adherent cells were isolated and cultured from bone marrow of five guinea pigs.The morphology of these cells was observed by microscope and the surface antigen was detected by flowcytometry with CD34,CD44 and CD45 antibody.BDNF gene was transfected to BMSCs with electroporation,the transfected BMSCs were induced by ratinoic acid(RA) after bolted by Geneticin-418(G418),then the differentiated BMSCs were identified by immunocytochemistry of neuron-specificenolase(NSE),Nestin and glial fibrillary acid protien(GFAP)antibody.
Results The culture cells had the typical morphology and surface antigen of BMSCs,the efficiency of human BDNF gene transfected BMSCs with electroporation was about 25%,the transfected cells were similar to nerve cells on appearance and could express NSE,Nestin and GFAP.
Conclusions BMSCs transfected by BDNF gene can differentiate into neuron-like cells in vitro,electroporation can boost the transfection efficiency,RA has the effect to promote induction.
PartⅢPreliminary observation of bone-marrow mesenchymal stem cells transplant into cochlea after transfected by brain-derived neurotrophic factor gene
Objective To investigate the function of differentiation and protection of bone-marrow mesenchymal stem cells(BMSCs) in damaged cochlea after transfected by human brain-derived neurotrophic factor (BDNF) gene.
Methods BMSCs were induced and marked after transfected by hBDNF gene in vitro.These BMSCs(BDNF- BMSCs) were transplanted into tympanic scala of the guinea pigs which were deafened by amikacin(AK).The control groups were designed in which artifical perilymphatic fluid(APF),BMSCs or BDNF gene was injected into cochlea alone.The cochlea was respectively obtained and in paraffin-embedded on the week 1,2 and 4 after injected,and cut in a paramodiolar plane subsequently.Histopathological changes were observed and analyzed by staining with HE,the density of SGNs was calculated,the BMSCs distribution was reviewed,differentiation of BMSCs in vivo and survival of SGNs was detected with immunohistochemistry of NSE,Nestin and GFAP antibody.
Results Construction of the guinea pig cochlea was damaged when amikacin was injected into abdominal cavity,the number of SGNs was decreased.
The result of immunochemistry analyzed with average optical density(AOD) showed:the AOD of the BDNF-BMSCs group in vivo was not obviously different from in vitro on 1W and 2W,but significantly reduced on 4W(P＜0.05),and was significantly higher than the BMSCs group on 1W,2W and 4W(P＜0.01)
BMSCs which were differentiated or not could survive and scatter over some areas in the cochlea.Some induced BMSCs were positive for NSE,Nestin and GFAP,while only a few uninduced BMSCs were positive BMSCs,BDNF gene or BDNF- BMSCs could all rival the ototoxicity of amikacin in the cochlea,the protection taken by BDNF-BMSCs was the most obvious.In the BDNF- BMSCs group it could be confirmed about SGNs that the morphous changed smallest,the density and average optical density for NSE was the highest.The difference was significant compared with the control groups(P＜0.05 )
Conclusions The differentiated ability of BMSCs induced by BDNF gene in vitro is invariable in about two weeks when they are transplanted into the cochlea,but reduces on 4W.The better protection of inner ear is confirmed when BDNF-BMSCs are transplanted into cochlea compared with transplanting BMSCs or BDNF gene alone.
引文
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