摘要
第一部分
猕猴胚胎源性神经干细胞的诱导分化、干性维持及脑内移植
目的：建立稳定高效的猕猴神经干细胞体外培养、诱导体系,使其可成功的分化及特性维持；观察研究猕猴神经干细胞同种脑内移植后的转归,进一步验证猕猴神经干细胞经体外培养、诱导后的特性及可应用性,为神经干细胞临床应用研究。
方法：1)以绿色荧光蛋白(Green fluorescence protein, GFP)为标记,探讨猕猴胚胎干细胞向玫瑰花环(Rosettes)结构神经干细胞的分化及其碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF)和表皮生长因子(Epidermal growth factor, EGF)的扩增培养；2)经立体定位,利用微量注射器,将5ul(1X105个/u1)神经干细胞移植到猕猴海马区,移植后2个月后,取脑组织冰冻切片,用免疫组织化学和激光共聚焦鉴定移植的神经干细胞在体内的存活与分化情况。
结果：1)建立了稳定高效的猕猴神经干细胞分化体系；2)分化得到的Rosettes结构神经干细胞经bFGF/EGF扩增后,能够较好的维持其Rosettes结构；3)神经干细胞移植到两只猕猴脑内后两个月,发现移植细胞能够较好的存活,并向神经元及神经胶质细胞分化。
结论：经bFGF/EGF扩增培养猕猴胚胎干细胞能较好的维持神经干细胞的Rosettes结构(真正意义上的早期全能神经前体细胞)；扩增培养的神经干细胞移植到两只猕猴脑内后能维持其特性,为将来神经干细胞应用于临床提供基础理论依据。
第二部分
神经干细胞移植对脑外伤大鼠神经功能恢复、细胞凋亡及凋亡基因表达的影响
目的：观察神经干细胞(NSCs)移植对脑损伤大鼠神经功能及细胞凋亡的影响,探讨其分子机制。
方法：24只SD大鼠随机分为3组：假手术组、手术组和NSCs移植组。采用自由落体致大鼠皮质运动区脑损伤模型,NSCs于术后当天移植入脑损伤大鼠挫伤位周围4个点；术后观察大鼠的神经功能恢复情况,移植的NSCs在脑组织存活、迁移及细胞凋亡、抗凋亡基因表达情况。
结果：NSCs移植后NSS评分至第7天明显比对照组下降,说明NSC移植对脑外伤大鼠神经功能有改善作用。移植NSCs能在宿主脑组织存活,并向四周迁移；凋亡细胞数量明显减少；而抗凋亡基因BCL-XL表达明显增加,与未移植NSCs的单纯手术组比较差异均有统计学意义。
结论：NSCs能改善脑损伤大鼠神经功能,其机制可能与NSCs在体内存活、能够减少细胞凋亡和增加抗凋亡基因BCL-XL表达有关。
第三部分
适用神经干细胞移植研究的青光眼视神经损伤模型的建立
目的：探索一种能够适用于干细胞移植研究的青光眼造模方法,为神经干细胞临床应用研究奠定模型基础。
方法：本实验采用对新西兰白兔球结膜下注射地塞米松注射液的方式给药,2.5mg/次,一周3次(间隔一天给药),持续8周。
结果：眼底照相观察到造模眼眼球屈光间质保持清晰,视乳头凹陷明显扩大、血管呈屈膝状；病理切片显示造模眼视神经受到明显损伤；海德堡视网膜断层扫描仪(Heidelberg Retina Tomography, HRT)定量分析显示造模眼呈现盘沿面积减小1.10±0.88mm2、杯/盘比增大0.17±0.13,以及视网膜神经纤维层平均厚度降低0.44±0.31mm的青光眼性质病理改变,均达到极显著水平(p<0.001)。
结论：1)本实验建立了一种简单可靠、重复性强的慢性青光眼视神经损伤的造模方法；2)造模眼眼压波动轻微,不会影响移植细胞的生长,眼底照相观察到造模眼眼球屈光间质保持清晰,适合观察神经干细胞移植后情况,此造模方法适用于干细胞移植研究。
第四部分兔青光眼视神经损伤后移植神经干细胞的探索研究
目的：探索青光眼视神经损伤后移植神经干细胞具体可行性。
方法：青光眼视神经损伤模型建立后,以不同的移植方法双眼(模型眼及对照眼)注入猕猴神经干细胞,植入5个月后,摘取眼球,采用不同标本制作方法,固定、切片,通过共聚焦显微镜观察神经干细胞生长存活情况,并观察其在眼内迁移及与视网膜整合情况,移植后眼内反应等。
结果：青光眼视神经损伤兔眼(模型眼)玻璃体内可见存活的神经干细胞,未见神经干细胞迁移及与视网膜整合,对照眼未见神经干细胞存活；此结果与移植方法、标本制作方法及免疫反应有关。
结论：猕猴神经干细胞能够在青光眼视神经损伤的兔眼玻璃体内长时间存活并生长,为后续研究奠定了基础,进一步证实了本实验第三部分的造模方法适合用于神经干细胞移植的研究；神经干细胞玻璃体移植后未见向视网膜迁移整合,提示对神经干细胞眼内注入方法需进一步改良研究；仅在模型眼(注射地塞米松)观察到神经干细胞玻璃体存活生长,对照眼未见,且有眼内反应现象,为下一步研究神经干细胞眼内移植后如何控制免疫排斥反应提供了思路。
第五部分
单侧青光眼视神经损伤后眼外肌及其本体感受器病理学改变
目的研究单侧青光眼视神经损伤后间歇性斜视(知觉性)患者眼外肌及其本体感受器的超微结构,以期了解青光眼视神经损伤患者眼运动系统的病理变化及探讨其发病机制,推进对青光眼神经疾病的认识,并为后续研究神经干细胞移植提供组织形态学基础。
方法选取10例单侧青光眼视神经损伤后间歇性(知觉性)外斜视患者非注视眼内直肌附着点后长约4-5mm,宽约1Omm的眼外肌作为实验组(光镜10例、透射电镜10例),选取10例同期角膜移植供体的健康人眼内直肌作为正常对照组(光镜5例、透射电镜5例),制作病理标本,光镜及透射电镜下观察比较2组肌纤维及眼外肌本体感受器的超微结构差异。
结果同正常对照组比较,单侧青光眼视神经损伤后间歇性(知觉性)外斜视患者眼外肌纤维排列紊乱,部分纤维萎缩、水肿,线粒体变性,眼外肌本体感受器结构出现明显异常,内外膜不完整,梭内肌纤维排列紊乱,有髓神经轴浆内有残体形成,线粒体缺如,内膜与Schwann细胞间可见粗大致密的胶原纤维增生,神经纤维内微丝、微管等细胞器减少,严重者可见有髓神经脱髓鞘。
结论单侧青光眼视神经损伤后眼外肌内直肌及其本体感受器发生了病理性改变,即眼运动神经通路的效应器出现了异常改变。
PART1The differentiation and proliferation of rhesus monkey embryonic stem cells and allotransplantation
Objective: To investigate the characteristics of proliferation and differentiation of the neural stem cells from rhesus monkey embryonic stem cells through establishing a stable and high-efficient neural differentiation system in vitro and observe the impact of nervous system function and apoptosis after neural stem cells (NSCs) transplantation in rats brain of cerebral contusion and explore the molecular mechanisms, promote the clinical application of neural stem cells.
Methods:The differentiation and proliferation of the GFP marked rhesus monkey embryonic stem cells with bFGF/EGF into rosettes neural stem cells, were studied in the present project; through the radiostereostatics,transplanted5ul (1X105/ul) neural stem cell to the hippocampus of rhesus monkey, made brain tissue frozen section after two months, identified the survival and differentiation of neural stem cells transplanted in the body with immunohistochemical and confocal laser.
Results:1) A stable and high-efficient neural differentiation system was established.2) The rosettes neural stem cells differentiated from the rhesus monkey embryonic stem cells could maintain the rosettes-shape (The true sense almighty neural progenitor cell) after proliferation with bFGF/EGF.3) After neural stem cell transplanted into two rhesus monkey brain two months, found that cell can survive, and differentiated into neurons and glial cells.
Conclusion:The rosettes neural stem cells differentiated from rhesus monkey embryonic stem cells could maintain its characteristics after proliferation with bFGF/EGF and it could survive and differentiate into neurons after transplanted into the rhesus monkey brain, which will be giving solid support to the clinical application of neural stem cells in the future.
PART2The influence of neurological function, apoptosis and gene expression after neural stem cells transplanted in rats with brain injury
Objective: To observe the impact of nervous system function and apoptosis after neural stem cells (NSCs) transplantation in rats brain of cerebral contusion and explore the molecular mechanisms.
Methods:24SD rats were randomly divided into three groups:sham group, the surgical group and NSCs transplantation group. Rats brain injury model of cortical motor area induced by freefalling, NSCs transplanted into in four points of rats injury brain, and observed recovery of neurological function and survival of transplanted NSCs in the brain tissue, migration and apoptosis, apoptotic gene expression.
Results:NSS score of the NSCs transplantation group significantly declined after7days; NSCs can survive and migrate in the host brain tissue; the number of apoptotic cells significantly reduced;BCL-XL expression was significantly increased, compared with the simply surgery group (not transplanted NSCs),the differences were statistically significant.
Conclusion:NSCs can improve the nerve function of brain contusion rats; NSCs can survive in vivo, reduced apoptosis and increased apoptotic gene BCL-XL expression.
PART3Glaucoma optic nerve injury model applied neural stem cell transplantation research
Objective: Investigate an appropriate method of modeling glaucoma for stem cells transplantation study and promote the clinical application of neural stem cells.
Methods:Dexamethasone was injected unilaterally into the conjunctiva of New Zealand rabbit at the dose of2.5mg (5mg/ml),3times a week (every other day in work days), had last for8weeks. Then neural stem cells were injected into the vitreous body of the model eye4mm behind the cornea rim, after5months, gathered the eyes, made pathological, and observed neural stem cell growth survival through the confocal microscopy.
Results:Eye ground photography showed that compared to the control eyes, the optic nerve head was expanded, the blood vessel was geniculate, while the ocular media kept transparent; hematoxylin-eosin (HE) stain of RNFL sections showed the optic neuron death of the model eyes. Heidelberg Retina Tomography (HRT) results showed consistent changes of the model eyes with pathophysiology of Glaucoma including, decrease1.10±0.88mm2in Rim area, increase0.17±0.13in Cup/disk ratio and decrease0.44±0.31mm in Mean retinal nerve fiber layer (RNFL) thickness, was different (p<0.001); And observed neural stem cells were survived in vitreous.
Conclusion:This chronic glaucoma mode made by this experiment is a simple and reliable, repeatability strong, and applies neural stem cell transplantation research; the intraocular pressure fluctuations with glaucoma optic nerve injury was minor and will not affect the growth of cells transplanted, this experiment keep eyes clear refractive, suitable for observation neural stem cells after transplantation
PART4The research of neural stem cells transplants in rabbit eyes with glaucoma optic nerve injury
Objective: To explore the specific feasibility about transplantation into eyes with glaucoma optic nerve injury.
Methods: After Animal models of glaucoma optic nerve injury were established, with different methods transplantating rhesus monkey neural stem cells into eyes (model eye and control eyes), after five months, and gathered the eye balls, using different methods of specimen, fixed, slice, through the confocal microscopy, observed growth, survival, the migration, integration and response of neural stem cell in the eye.
Results:The live neural stem cells were visible in the vitreous body of rabbit eyes (model eyes)with glaucoma optic nerve injury, did not observed the migration and integration of the neural stem cells, there was not the neural stem cells in control eyes; The results were related to transplantation methods, specimen production methods and the immune response.
Conclusion:The rhesus monkey neural stem cells can better survived in the vitreous body of rabbit eyes with glaucoma optic nerve injury, were the foundation for the follow-up studies, further proof that the third part of the experiment was suitable for neural stem cell transplantation research; the rhesus monkey neural stem cells transplanted in vitreous did not migrate and integrate into the retina, transplantation method should be further improved; the live growth of neural stem cells were only observed in the model eyes (injection dexamethasone), did not observe in control eyes, and found response phenomenon in eyes, this give us new think about how to control the immune rejection response for the next step study.
PART5Pathological changes of extraocular muscule and proprioceptors in extraocular muscles of the patients with monocular glaucoma damage
Objective: To observe the ultrastructure of extraocular muscle (EOM) and proprioceptors in extraocular muscles (EMP) in intermittent exotropia (sensory strabismus) with monocular glaucoma damage and discuss it's etiology and pathothogenesis. Promote the further understanding of glaucoma nerve disease, and provides tissue morphological basis for follow-up study of neural stem cell transplantation.
Methods: The samples were obstained from medial rectus of10patients who were suffering from intermittent exotropia with monocular glaucoma damage, were about4-5mm, width of10mm of eye muscles as the experimental group (10cases, light microscopy, transmission electron microscopy,10cases),10corneal graft donors were as the normal control group (5cases by light microscopy,5cases by transmission electron microscopy), after being stained pathological specimens,the samples were examined under light microscopy(LM) and transmission electron microscopy(TEM)to observe the structure of extraocular muscle and EMP of two groups.
Results:Compared with normal control group, the muscle fibers of medial rectus of the patients with intermittent exotropia and monocular glaucoma damage arranged disorderly, showed atrophied and edema, mitochondrial degeneration, the proprioceptors in extraocular muscle from intermittent exotropia showed ultrastructual change, inner and outer membranes were incomplete, intraspindle muscle fibers arranged disorderly,the formation of residues were found in myelinated nerve axoplasmic,lack of mitochondria, the thick dense collagen fiber hyperplasia appeared between Schwann cells and inner membrane, microfilaments and microtubules of the nerve fibers decreased, and nerve demyelination in severe cases.
Conclusion:The ultrastructure of medial rectus of patients with intermittent exotropia was pathological changed compared with that of the controls. The motor pathways of the monocular glaucoma damage showed ultrastructual change.
引文
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