骨髓间充质干细胞移植治疗帕金森病的基础研究
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摘要
目的:评估骨髓间充质干细胞(BMSCs)移植治疗帕金森病的效果,探讨其作用机制,并比较两种移植途径对疗效的影响,为干细胞移植治疗帕金森病提供理论基础。探讨活体成像监测荧光细胞变化趋势的条件。
方法:建立帕金森病(PD)大鼠模型,随机分为三组:颅内注射组——应用立体定位技术将BMSCs移植到PD大鼠的纹状体内;静脉注射组——经尾静脉输注BMSCs悬液;空白对照组——纹状体内(注射点同颅内注射组)注入生理盐水。利用BMSCs贴壁生长的特性筛选、扩增大鼠骨髓间充质干细胞。应用携带绿色荧光蛋白(GFP)基因的病毒载体转染BMSCs。
应用UVP活体成像系统,测定GFP标记BMSCs荧光成像的灰度值,建立BMSCs细胞数量与成像面积密度的拟合曲线。对行GFP标记BMSCs移植治疗的PD大鼠成像,应用拟合曲线计算大鼠脑组织内2周、4周及8周时BMSCs的存活情况。
从不同层面分析移植BMSCs对PD大鼠的作用,探讨BMSCs的作用机制:(1)检测PD大鼠移植BMSCs后2周、4周及8周阿朴吗啡(APO)诱导的旋转行为变化,评估BMSCs的治疗效果及组间差异。(2)高效液相色谱-电化学法(HPLC-ECD)检测BMSCs移植前后不同组别PD大鼠脑内多巴胺(DA)及其代谢产物二羟苯乙酸(DOPAC)、高香草酸(HVA)含量,判定DA分泌功能状况,分析疗效。(3)病理检测移植后的BMSCs细胞形态及周围组织变化;荧光免疫组织化学法证实移植BMSCs的分化方向。
结果:GFP标记大鼠BMSCs可以稳定传代,冻存、复苏后仍保持GFP表达。UVP成像技术测得的成像面积密度与荧光细胞数量呈良好的线性关系。BMSCs移植后PD大鼠经UVP成像,应用拟合曲线半定量测定大鼠脑组织内存活GFP-BMSCs的数量,可见其随移植时间的延长而逐渐降低。
BMSCs移植后第2、4及8周,以APO诱导PD大鼠出现旋转行为,发现颅内注射组、静脉注射组PD大鼠旋转次数均较空白对照组显著减少(p＜0.05);颅内注射组较静脉注射组显著减少(p＜0.05);颅内注射组及静脉注射组均较BMSCs移植前显著减少(p＜0.05)。
BMSCs移植后4周HPLC检测结果显示,颅内注射组、静脉注射组DA及其代谢产物DOPAC、HVA含量均高于空白对照组(p＜0.05);颅内注射组DA、DOPAC、HVA含量高于静脉注射组(p＜0.05)。
大鼠脑组织切片显示,颅内注射组和静脉注射组脑组织形态结构较空白对照组无明显变化,未见炎细胞浸润和毛细血管充血等现象,未见移植BMSCs过度增殖。BMSCs注射后2、4与8周,颅内注射组、静脉注射组大鼠脑组织内均可见GFP标记细胞,颅内注射组毁损区对侧脑内可见少量GFP标记细胞。免疫组化显示,BMSCs注射后4周、8周,颅内注射组和静脉注射组大鼠脑组织内多巴胺能神经元细胞标志物TH-1的表达显著高于空白对照组,以颅内注射组TH-1表达增多更为显著,可见GFP/TH-1双阳性细胞;颅内注射组和静脉注射组大鼠脑组织内星形胶质细胞标志物GFAP的表达显著高于空白对照组,颅内注射组和静脉注射组无显著差异,可见GFP/GFAP双阳性细胞;颅内注射组和静脉注射组大鼠脑组织内NSE的表达显著高于空白对照组,以颅内注射组NSE表达增多更为显著,可见GFP/NSE双阳性细胞。
结论:(1)BMSCs移植治疗PD大鼠有效、安全。BMSCs移植后帕金森病大鼠的行为学障碍出现改善,移植后的BMSCs可在脑组织内长期存活,无致炎性,无过度增殖。(2)BMSCs移植治疗PD的可能作用机制:移植BMsCs分化成多巴胺能神经元而起替代作用;移植BMSCs分化为星形胶质细胞而释放神经营养因子,修复损伤;移植BMSCs提供了一个有利于病变组织修复的微环境。(3)颅内定点移植与静脉移植都能够产生积极的治疗作用,但前者效果优于后者。(4)UVP活体成像系统能够半定量细胞的数量、追踪其变化趋势。
Objective:To explore the effect and the mechanism of BMSCs transplantation in Parkinson's disease.At the same time,to evaluate the difference between the two approaches of transplantation.To grope the stratagem of tracking living fluorescent cells by using UVP Imagining system.
Methods:PD rat models were established,and randomized into three groups on the basis of BMSCs-transplanted approach:brain-approach group,vein-approach group and controlled group.Based on the adherent characteristic,rat BMSCs were cultured and purified.Then they were marked by GFP through viral vector.
The gray scale of GFP-BMSCs imagines made by UVP LS Imageing system was measured;as a result,the regression curve of the GFP-cells' amount and area density was deduced.According to the curve,the amount of living transplanted GFP-BMSCs was calculated at the different intervals after BMSCs transplantation.
The effect and mechanism were explored from different aspects.(1) APO-induced rotation was quantified at 2,4 and 8 weeks after BMSCs transplantation to evaluate the therapy effect.(2) The level of DA and its' metabolin,DOPAC and HVA,in different groups was detected by HPLC-ECD to analysis the secret- function of dopaminergic neuron.(3) The cell morphology of transplanted BMSCs was observed,and so did the surrounding tissue.The differentiation of transplanted BMSCs was witnessed by fluorescent immunohistochemistry.
Results:Rat BMSCs marked by GFP could be cultured stably,and GFP gene could be well expressed after freezing and thawing.Living fluorescent cells had fine linear correlation with area density.The number of living transplanted GFP-BMSCs in PD rat model was semiquantified,and it degraded along with the interval prolonged after transplantation.
APO-induced rotation of PD rat was significantly reduced in brain-approach group and vein-approach group compared with controlled group 2,4 and 8 weeks after BMSCs transplantation(p＜0.05),and so did brain-approach group compared with vein-approach group(p＜0.05).It was also observed that after BMSCs transplanted,APO-induced rotation in brain-approach and vein-approach significantly reduced compared with pre-transplantation(p＜0.05).
The level of DA and DOPAC,HVA in brain-approach group and vein-approach group was higher than controlled group(p＜0.05) while brain-approach group was higher than vein-approach group(p＜0.05).
No apparent change,such as inflammation or over proliferation,was observed in the surrounding tissue in the three groups.2,4 and 8 weeks after transplantation,GFP-positive cells were found in cerebrum both in brain-approach group and vein-approach group.GFP-positive cells were found in the opposite hemisphere in brain-approach group.4 and 8 weeks after transplantation,the expression of TH-1 in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),particularly brain-approach group.Double positive cells(GFP~+/TH-1~+) were founded in both groups.The expression of GFAP in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),and double positive cells(GFP~+/GFAP~+) were founded in both groups.The expression of NSE in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),particularly brain-approach group.Double positive cells(GFP~+NSE~+) were founded in both groups.
Conclusions:(1) BMSCs transplantation is an effective and safe therapy for PD rat models.(2) The mechanism of the therapy includes the substitution of differentiated dopaminergic neurons coming from transplanted BMSCs and nutritional effect of differentiated astrocytes coming from transplanted BMSCs. Furthermore,transplanted BMSCs provide a microenvironment which is suitable for repairing damage.(3) Both the brain-approach and the vein-approach are benefit for PD therapy,but the former is better than the later.(4) UVP LS imaging system can semiquantitative and track fluorescent cells.
方法:建立帕金森病(PD)大鼠模型,随机分为三组:颅内注射组——应用立体定位技术将BMSCs移植到PD大鼠的纹状体内;静脉注射组——经尾静脉输注BMSCs悬液;空白对照组——纹状体内(注射点同颅内注射组)注入生理盐水。利用BMSCs贴壁生长的特性筛选、扩增大鼠骨髓间充质干细胞。应用携带绿色荧光蛋白(GFP)基因的病毒载体转染BMSCs。
应用UVP活体成像系统,测定GFP标记BMSCs荧光成像的灰度值,建立BMSCs细胞数量与成像面积密度的拟合曲线。对行GFP标记BMSCs移植治疗的PD大鼠成像,应用拟合曲线计算大鼠脑组织内2周、4周及8周时BMSCs的存活情况。
从不同层面分析移植BMSCs对PD大鼠的作用,探讨BMSCs的作用机制:(1)检测PD大鼠移植BMSCs后2周、4周及8周阿朴吗啡(APO)诱导的旋转行为变化,评估BMSCs的治疗效果及组间差异。(2)高效液相色谱-电化学法(HPLC-ECD)检测BMSCs移植前后不同组别PD大鼠脑内多巴胺(DA)及其代谢产物二羟苯乙酸(DOPAC)、高香草酸(HVA)含量,判定DA分泌功能状况,分析疗效。(3)病理检测移植后的BMSCs细胞形态及周围组织变化;荧光免疫组织化学法证实移植BMSCs的分化方向。
结果:GFP标记大鼠BMSCs可以稳定传代,冻存、复苏后仍保持GFP表达。UVP成像技术测得的成像面积密度与荧光细胞数量呈良好的线性关系。BMSCs移植后PD大鼠经UVP成像,应用拟合曲线半定量测定大鼠脑组织内存活GFP-BMSCs的数量,可见其随移植时间的延长而逐渐降低。
BMSCs移植后第2、4及8周,以APO诱导PD大鼠出现旋转行为,发现颅内注射组、静脉注射组PD大鼠旋转次数均较空白对照组显著减少(p＜0.05);颅内注射组较静脉注射组显著减少(p＜0.05);颅内注射组及静脉注射组均较BMSCs移植前显著减少(p＜0.05)。
BMSCs移植后4周HPLC检测结果显示,颅内注射组、静脉注射组DA及其代谢产物DOPAC、HVA含量均高于空白对照组(p＜0.05);颅内注射组DA、DOPAC、HVA含量高于静脉注射组(p＜0.05)。
大鼠脑组织切片显示,颅内注射组和静脉注射组脑组织形态结构较空白对照组无明显变化,未见炎细胞浸润和毛细血管充血等现象,未见移植BMSCs过度增殖。BMSCs注射后2、4与8周,颅内注射组、静脉注射组大鼠脑组织内均可见GFP标记细胞,颅内注射组毁损区对侧脑内可见少量GFP标记细胞。免疫组化显示,BMSCs注射后4周、8周,颅内注射组和静脉注射组大鼠脑组织内多巴胺能神经元细胞标志物TH-1的表达显著高于空白对照组,以颅内注射组TH-1表达增多更为显著,可见GFP/TH-1双阳性细胞;颅内注射组和静脉注射组大鼠脑组织内星形胶质细胞标志物GFAP的表达显著高于空白对照组,颅内注射组和静脉注射组无显著差异,可见GFP/GFAP双阳性细胞;颅内注射组和静脉注射组大鼠脑组织内NSE的表达显著高于空白对照组,以颅内注射组NSE表达增多更为显著,可见GFP/NSE双阳性细胞。
结论:(1)BMSCs移植治疗PD大鼠有效、安全。BMSCs移植后帕金森病大鼠的行为学障碍出现改善,移植后的BMSCs可在脑组织内长期存活,无致炎性,无过度增殖。(2)BMSCs移植治疗PD的可能作用机制:移植BMsCs分化成多巴胺能神经元而起替代作用;移植BMSCs分化为星形胶质细胞而释放神经营养因子,修复损伤;移植BMSCs提供了一个有利于病变组织修复的微环境。(3)颅内定点移植与静脉移植都能够产生积极的治疗作用,但前者效果优于后者。(4)UVP活体成像系统能够半定量细胞的数量、追踪其变化趋势。
Objective:To explore the effect and the mechanism of BMSCs transplantation in Parkinson's disease.At the same time,to evaluate the difference between the two approaches of transplantation.To grope the stratagem of tracking living fluorescent cells by using UVP Imagining system.
Methods:PD rat models were established,and randomized into three groups on the basis of BMSCs-transplanted approach:brain-approach group,vein-approach group and controlled group.Based on the adherent characteristic,rat BMSCs were cultured and purified.Then they were marked by GFP through viral vector.
The gray scale of GFP-BMSCs imagines made by UVP LS Imageing system was measured;as a result,the regression curve of the GFP-cells' amount and area density was deduced.According to the curve,the amount of living transplanted GFP-BMSCs was calculated at the different intervals after BMSCs transplantation.
The effect and mechanism were explored from different aspects.(1) APO-induced rotation was quantified at 2,4 and 8 weeks after BMSCs transplantation to evaluate the therapy effect.(2) The level of DA and its' metabolin,DOPAC and HVA,in different groups was detected by HPLC-ECD to analysis the secret- function of dopaminergic neuron.(3) The cell morphology of transplanted BMSCs was observed,and so did the surrounding tissue.The differentiation of transplanted BMSCs was witnessed by fluorescent immunohistochemistry.
Results:Rat BMSCs marked by GFP could be cultured stably,and GFP gene could be well expressed after freezing and thawing.Living fluorescent cells had fine linear correlation with area density.The number of living transplanted GFP-BMSCs in PD rat model was semiquantified,and it degraded along with the interval prolonged after transplantation.
APO-induced rotation of PD rat was significantly reduced in brain-approach group and vein-approach group compared with controlled group 2,4 and 8 weeks after BMSCs transplantation(p＜0.05),and so did brain-approach group compared with vein-approach group(p＜0.05).It was also observed that after BMSCs transplanted,APO-induced rotation in brain-approach and vein-approach significantly reduced compared with pre-transplantation(p＜0.05).
The level of DA and DOPAC,HVA in brain-approach group and vein-approach group was higher than controlled group(p＜0.05) while brain-approach group was higher than vein-approach group(p＜0.05).
No apparent change,such as inflammation or over proliferation,was observed in the surrounding tissue in the three groups.2,4 and 8 weeks after transplantation,GFP-positive cells were found in cerebrum both in brain-approach group and vein-approach group.GFP-positive cells were found in the opposite hemisphere in brain-approach group.4 and 8 weeks after transplantation,the expression of TH-1 in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),particularly brain-approach group.Double positive cells(GFP~+/TH-1~+) were founded in both groups.The expression of GFAP in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),and double positive cells(GFP~+/GFAP~+) were founded in both groups.The expression of NSE in brain-approach group and vein-approach group was higher than controlled group(p＜0.05),particularly brain-approach group.Double positive cells(GFP~+NSE~+) were founded in both groups.
Conclusions:(1) BMSCs transplantation is an effective and safe therapy for PD rat models.(2) The mechanism of the therapy includes the substitution of differentiated dopaminergic neurons coming from transplanted BMSCs and nutritional effect of differentiated astrocytes coming from transplanted BMSCs. Furthermore,transplanted BMSCs provide a microenvironment which is suitable for repairing damage.(3) Both the brain-approach and the vein-approach are benefit for PD therapy,but the former is better than the later.(4) UVP LS imaging system can semiquantitative and track fluorescent cells.
引文
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49.Siderowf A,Stem M.Update to Parkinson disease[J].Ann Inter Med,2003,138(8):651-658
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51.Bowers W J,Howard D F,Federroff H J.Gene therapeutic state gies for neuroprotection: implications for Parkinson's disease[J].Exp Neurol,1997,144(11):58-62
52.Gao J,Zhang HJ.The characteristics of Anti-Parkinson drugs[J].Chin J Clin Rehabil,2002,6(14):212
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55.Lindvall O,Rehncrona S,Gustuvii B,et al.Fetal dopamine-rich mesencephalic grafts in parkinson's disease[J].Lancet,1988;2(8626-8627):1483-1484
56.Freed CR,Greene PE,Breeze RE,et al.Transplantation of embryonic dopamine neurons for severe Parkinson's disease[J].N Engl J Med,2001,344:710-719
57.Bjorklund A,Lindvall O.Cell replacement therapies for central nervous system disorders[J].Nature Neurosci,2003;3(6):537-544
58.Lindvall O,Kokaia Z,Martinez-Serrano.Stem cell therapy for human neruodegenerative disorders-how to make it work.Nature Med 2004;10:542-550
59.Mckay R.Enhance proliferation,survival,and dopaminergic differentiation of CNS precursors in lowered oxygen[J].Neurosci,2000;20(19):7377-7384
60.Keller GEmbryonic stem cell differentiation:emergence of a new era in biology and medicine.Genes Dev,2005;19(10):1129-1155
61.Evans MJ,Kauman M.Establishiment in culture of pluripotent cells from mouse embryos.Nature,1981,292:154
62.Lee SA,Lumelsky N,Studer L,et al.Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.[J].Nat Biotechnol,2000;18(6):675-679
63.Kawasaki H,Mizuseki K,Nishikawa S,et al.Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity.[J].Neuron,2000;28(l):31-40
64.Mimura T,Dezawa M,Kanno H,et al.Behavioral and histological evaluation of a focal cerebral rat model transplanted with neurons induced from bone marrow stromal cells.J Neuropathol Exp Neurol.2005;64(12):1108-1117
65.Bjorklund LM,Sanchez-Pernaute R,Chung S,et al.Embryonic stem cells develop into functional dopaminergic neurons after transfplantation in a Parkinson rat model.Proc Natl Acad Sci USA 2002;99(4):2344-2349
66.Takagi Y,Takahashi J,Saiki H,et al.Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model[J].J Clin Invest,2005;115(1):102-109
67.Langston JW.The paomise of stem cells in Parkinson disease[J].J Clin Inves,2005,115(1):23-25
68.Piccini P,Brooks DJ,Bjorklund A,et al.Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient.Nat Neurosci,1999,2(12):1137-1140
69.田增民,刘爽,李士月,等.人神经干细胞临床移植治疗帕金森病[J].第二军医大学学报,2003,24(9):957-959
70.Reynolds BA,Weiss S.Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.Science.1992 Mar 27;255(5052):1707-1710
71.Mckay R.Stem cells in the central nervous system.Science,1997,276:66-71
72.Kalyani AJ,Piper D,Mujtaba T,et al.Spinal cord neuronal precursors generate multiple neuronal phenotypes in culture[J].J Neurosci,1998,18:7856-7868
73.Reynolds BA,Weiss S.Generation of neurons and astrocytes from isolated of the adult mammalian central nervous system[J].Science,1992,255:1707-1710
74.Ling ZD,Potter ED,Lipton JW,et al.Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines[J].Exp Neurol,1998,149:411-423
75.Vescovi AL,Parati EA,Gritti A,et al.Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation[J].Exp Neurol,2001,1711:98-108
76.Armstrong RF,Hurelbrink CB,Tyers P,et al.The potential for circruit reconstruction by expanded neural precusor cells explored through porcine xenografts in a rat model of Parkinson's disease[J].Exp Neurol,2002,175:98-111
77.Parati EA,Bez A,Ponti D,et al.Neural stem cells.Biological features and therapeutic potential in Parkinson's disease[J].J Neurosurg Sci,2003,47(l):8-17
78.Lindball O,Hagell P.Cell replacement therapy in human neurodegenerative disorders.Clinical Neurosci Res,2002,2:86-92
79.Petersen BE,Bowen WC,Patrene KD,et al.Bone marrow as a potential source of hepatic oval cells.Science.1999 May 14;284(5417):1168-1170
80.Woodbury D,Schwarz EJ,Prockop DJ,et.al.Adult rat and human bone marrow stromal cells differentiate into neurons.J Neurosci Res.2000 Aug 15;61(4):364-370
81.Sanchez-Ramos J,Song S,Cardozo-Pelaez F,et al.Adult bone marrow stromal cells differentiate into neural cells in vitro.Exp Neurol.2000 Aug;164(2):247-256
82.Yano S,K.uroda S,Lee JB,et al.In vivo fluorescence tracking of bone marrow stromal cells transplanted into a pneumatic injury model of rat spinal cord.J Neurotrauma.2005;22(8):907-918
83.Hellmann MA,Panet H,Barhum Y,et al.Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents.Neurosci Lett,2006;395:124-128
84.Li Y,Chen J,Wang L,et al.Intracerebral transplantation of bone marrow stromal cells in a l-methyl-4-phenyl-l,2,3,6-terahydropyridine mouse model of Parkinson's disease.Neurosci Lett,2001;316(2):67-70
85.Kim TE,Lee HS,Lee YB,et al.Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurrl-overexpressing neural stem cell.Biochem Biophys Res Commun.2003 Jun 13;305(4):1040-1048
86.Yamada H,Dezawa M,Shimazu S,et al.Transfer of the von Hippel-Lindau gene to neuronal progenitor cells in treatment for Parkinson's disease.Ann Neurol.2003 Sep;54(3):352-359
87.Lu LL,Chunl LZ,Yu JL,et al.Therapeutic benefit of TH-engineered mesenchymal stem cells for Parkinson's disease[J].Brain Research Protocols,2005,15(4):46-51
88.Pisati F,Bossolasco P,Meregalli M,et al.Induction of neurotrophin expression via human adult mesenchymal stem cells:implication for cell therapy in neurodegenerative diseases.Cell Transplant.2007;16(1):41-55
89.Wagers AJ,Sherwood RI,Christensen JL,et al.Little evidence for developmental plasticity of adult hematopoietic stem cells[J].Science,2002,297(5590):2256-2259
90.Terada N,Hamazaki T,Oka M,et al.Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion[J].Nature,2002;416(6880):542-545
91.Crigler L,Robey RC,Asawachaicham A,et al.Human mesenchymal stem cells subpopulation express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis.Exp Neurol.2006;198:54-64
92.Mcleod M,Hong M,Mukhida K,et al.Erythropoietin and GDNF enhance ventral mesencephalic fiber outgrowth and caplillary proliferation following neural transplantation in rodent model of parkinson's disease.Eur J Neurosci,2006(24):361-370
93.Kitayama T,Onitsuka Y,Song L,et al.Assessing an eating disorder induced by 6-OHDA and the possibility of nerve regeneration therapy by transplantation of neural progenitor cells in rats.Nihon Shinkei Seishin Yakurigaku Zasshi.2007 Jun;27(3):109-116
94.Zhao M,Momma S,Delfani K,et al.Evidence for neurogenesis in the adult mammalian substantia nigra.Proc Natl Acad Sci U S A.2003 Jun 24;100(13):7925-7930
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