神经干细胞移植对脊髓损伤后PLP基因表达的影响

目的：研究神经干细胞(NSCs)移植对大鼠脊髓损伤(SCI)后髓鞘蛋白前脂蛋白(PLP)基因表达的影响，探讨神经干细胞移植促进大鼠SCI后髓鞘再生的机制。方法：NSCs由5-溴-2脱氧尿嘧啶核苷标记法(Brdu)标记。实验分为3组：NSCs移植组(A组)、DMEM填充组(B组)、正常对照组(C组)。大鼠SCI后第7d移植NSCs，应用免疫组化和RT—PCR法观察NSCs移植后是否存活，以及大鼠脊髓损伤区PLP基因表达的动态变化。结果：NSCs移植后在受体脊髓内存活，NSCs移植组较单纯损伤组明显促进了PLP基因在分子和蛋白水平的表达。结论：NSCs移植后可存活并促进PLP基因的表达，是促进脊髓损伤后髓鞘再生的机制之一。     

Present situation and future aspects of spinal cord regeneration

The central nervous system (CNS) has a limited capacity for regeneration after injury. In spinal cord injury (SCI) patients, total loss of all motor and sensory function occurs below the level of injury. Advances in treatment are expected for orthopedic and spinal surgeons. Recently, evidence of axonal regeneration and functional recovery has been reported in animal spinal cord injury models. Our studies on the roles of inhibitory molecules with a comparison between neonatal and adult animals may help serve as therapeutic targets to enhance axonal regeneration for the injured spinal cord. Also, our cell replacement study indicates the possibility of transplanting neural stem cells to supply the cell source for immature oligodendrocytes, which are thought to be essential for both the myelination and trophic support of regenerating axons in the spinal cord. Administration of neurotrophic factors, prevention of inhibitory factors, and stem cell technology have clinical applications in SCI patients. However, spinal cord regeneration involves a multistep process, and several factors have to be controlled after injury. A combination of several treatments could overcome a nonpermissive environment for spinal cord regeneration. Further understanding of the mechanisms and finding optimal targets of spinal cord regeneration are necessary to obtain successful therapies for SCI patients.Presented at the 76th Annual Meeting of the Japanese Orthopaedic Association, Kanazawa, Japan, May 23, 2003     

胶质细胞源性神经营养因子对大鼠脊髓损伤后运动功能的影响

目的:研究胶质细胞源性神经营养因子（GDNF）对大鼠脊髓损伤后后肢运动功能恢复的影响。方法:采用改良Nystr(?)m法后路压迫大鼠胸段脊髓造成损伤模型,经蛛网膜下腔置管局部连续给予NGF （10μg/d）或GDNF（10μg/d）1周,对照组给予生理盐水。伤后4周3组分别观测:①伤段脊髓残存组织面积;②采用斜板试验和运动功能评分观察大鼠后肢运动功能恢复情况。结果:大鼠脊髓损伤后4～14d,GDNF治疗组后肢运动功能评分明显高于NGF组和生理盐水对照组（P<0.05）。伤后28d GDNF组伤段残存脊髓组织面积大于对照组和NGF组（P<0.01）。结论:外源性GDNF能减少脊髓损伤后伤区的坏死、萎缩并促进大鼠后肢运动功能的早期恢复。     

不同途径移植自体激活雪旺细胞修复大鼠脊髓损伤

目的 通过不同途径移植自体激活雪旺细胞(autologous activated Schwann cells,AASCs),评价各种移植途径在修复脊髓损伤中的作用.方法 结扎Wistar大鼠双侧隐神经,1周后取下结扎处远端神经,在体外分离、培养、传代、纯化和鉴定后获得供实验用AASCs.60只Wistar大鼠制成T_(10)脊髓损伤模型后随机分为三组,1周后将预先用Hoechst33342标记的AASCs移植到三组大鼠体内:Ⅰ组,尾静脉移植;Ⅱ组,鞘内移植(经蛛网膜下腔);Ⅲ组,局部损伤处移植.术后采用BBB评分评价大鼠功能恢复.3个月后行BDA皮质脊髓束顺行示踪标记.标记2周后处死动物,取出损伤处脊髓行快速冰冻切片,行Cy3荧光探针染色、神经丝蛋白200(NF200)和HE染色.结果 AASCs在体外可稳定传4代以上,并表达S-100抗原.从术后第4周开始,BBB评分在各组间差异有统计学意义.至实验结束时,HE染色显示Ⅲ组中损伤空洞明显小于其余两组,NF200免疫组化染色阳性面积占总面积百分比各组间差异有统计学意义.BDA神经示踪显示,Ⅲ组中有较多的再生轴突通过脊髓损伤区,横断面上再生轴突的免疫组化阳性面积各组间差异有统计学意义.结论 局部损伤处移植AASCs可以有效保证移植细胞的数量,AASCs通过分泌多种营养因子和桥接损伤轴突再生的作用促进大鼠脊髓损伤后的功能恢复.     

嗅鞘细胞移植对大鼠损伤脊髓组织中BDNF表达的影响及意义

目的 观察嗅鞘细胞(OEC)移植治疗大鼠脊髓损伤的作用以及脊髓损伤组织中脑源性神经营养因子(BDNF)表达的变化,从神经营养因子角度探讨OEC移植修复脊髓损伤的机制.方法 分离和培养绿色荧光蛋白转基因大鼠的OEC,备移植用.取SD大鼠制备脊髓损伤模型,用随机数字表法将建模成功后的SD大鼠分为2组.实验组:建模成功后立即进行OEC移植,移植部位为脊髓损伤处及其首尾正中血管的左右两侧;对照组:用DMEM/F12培养液替代OEC悬液,操作同实验组.移植后对各组大鼠的运动功能进行评分,每周1次.采用实时逆转录聚合酶链反应检测BDNF mRNA的表达,采用免疫组织化学法检测BDNF蛋白的表达,取正常SD大鼠BDNF mRNA和蛋白的检测水平作为正常对照.结果 移植后两组大鼠的运动功能均逐渐改善,移植后21 d时,实验组大鼠运动功能评分明显高于对照组(P＜0.05).移植后OEC存活良好,实验组损伤的脊髓组织周围分布有大量的呈绿色荧光的OEC.移植后21 d时,实验组BDNF mRNA和蛋白的表达水平显著高于对照组和正常对照组(P<0.05),而对照组也显著高于正常对照组(P<0.05).结论 OEC移植可明显修复大鼠的脊髓损伤,其机制可能与OEC通过增强损伤脊髓组织中BDNF mRNA和蛋白的表达,改善局部微环境有关.

Abstract：

Objective To observe the expression of brain-derived neurotrophical factor (BDNF) in injury spinal cord after transplantation olfactory ensheathing cells (OECs), and to investigate the mechanism of OECs repairing spinal cord injury.Methods OECs from GFP transgenic rats were separated and cultured for transplantation. Spinal cord injury rats were separated two groups by random digits table. In experimental group, OECs suspension were transplanted into injured spinal cord following spinal cord injury. In control group, DMEM was transplanted into the injured spinal cord after spinal cord injury. Motor function was evaluated per week after transplantation. The expression levels of BDNF mRNA and protein were detected by using RT-PCR and immunohistochemistry respectively, and compared with those from normal SD rats.Results Motor function of two groups was improved gradually after transplantation. The motor function scores in experimental group was obviously higher than in control group at 21st day after transplantation (P<0.05). A lot of survival GFP OECs distributed around impaired myeloid tissue. At 21st day after transplantation, BDNF mRNA and protein expression in experimental group were strongest (P<0.05), and stronger in control group than in normal group (P<0.05).Conclusion The transplantation of OECs can repair the injured spinal cord by increasing the expression of BDNF mRNA and protein to improve local microenvironment.     

Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury

Stem/progenitor cells derived from the ependymal region of the spinal cord have the ability to self-renew and are multipotential for neurons and glia. These cells may have the ability to regenerate the injured mammalian spinal cord as they do in some lower vertebrates. However, the optimal conditions for transplantation and the fate of transplanted cells are not fully known. In the current study, spinal cord stem/progenitor cells were cultured from adult male rats expressing enhanced green fluorescent protein (eGFP). Neurospheres were transplanted at the time of clip compression injury (35-g force) into the injury site, or 1 mm rostral and caudal to the injury site. Neurospheres were also transplanted into a subacute model (day 9 after injury) and a chronic model (day 28 after injury). Functional recovery was also studied in an acute injury model with weekly locomotor testing over a 16-week period. A significant increase in cell survival at 7 days was seen in rats receiving rostral and caudal injections as compared to injection directly into the site of injury. A significant increase in cell survival was also seen in rats receiving subacute transplants at 9 days after injury. Transplanted cells differentiated primarily into astrocytes (31.2%) and oligodendrocytes (50.3%), and a small number of neurons (1%). No improvement was seen in the Basso, Beattie and Bresnahan (BBB) locomotor rating scale after acute transplantation as compared with injury only, although surviving transplanted cells were identified that had migrated across the injury site from the rostral and caudal injection sites.     

Transplantation of oligodendrocyte precursor cells improves myelination and promotes functional recovery after spinal cord injury

Loss of oligodendrocytes and demyelination further impair neural function after spinal cord injury (SCI). Replacement of lost oligodendrocytes and improvement of myelination have a therapeutic significance in treatment of SCI. Here, we transplanted oligodendrocyte precursor cells (OPCs) to improve myelination in a rat model of contusive SCI. The labelled OPCs were transplanted to injured cord 7 days after injury. As a result, the implanted cells still survived in vivo 8 weeks after transplantation. They proliferated, integrated and differentiated in the injured cord. In the OPCs-treated rats, enhanced myelination in the lesioned area was observed and substantial improvement of motor function and nerve conduction was also recorded. Thus, this study provides strong evidence to support that transplantation of OPCs could improve myelination of injured cord and enhance functional recovery after contusive SCI.     

Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat

Summary There have been many efforts to recover neuronal function from spinal cord injuries, but there are some limitations in the treatment of spinal cord injuries.The neural stem cell has been noted for its pluripotency to differentiate into various neural cell types. The human umbilical cord blood cells (HUCBs) are more pluripotent and genetically flexible than bone marrow neural stem cells. The HUCBs could be more frequently used for spinal cord injury treatment in the future.Moderate degree spinal cord injured rats were classified into 3 subgroups, group A: media was injected into the cord injury site, group B: HUCBs were transplanted into the cord injury site, and group C: HUCBs with BDNF (Brain-derived neutrophic factor) were transplanted into the cord injury site. We checked the BBB scores to evaluate the functional recovery in each group at 8 weeks after transplantation. We then, finally checked the neural cell differentiation with double immunofluorescence staining, and we also analyzed the axonal regeneration with retrograde labelling of brain stem neurons by using fluorogold. The HUCBs transplanted group improved, more than the control group at every week after transplantation, and also, the BDNF enabled an improvement of the BBB locomotion scores since the 1 week after its application (P<0.05). 8 weeks after transplantation, the HUCBs with BDNF transplanted group had more greatly improved BBB scores, than the other groups (P<0.001). The transplanted HUCBs were differentiated into various neural cells, which were confirmed by double immunoflorescence staining of BrdU and GFAP & MAP-2 staining. The HUCBs and BDNF each have individual positive effects on axonal regeneration. The HUCBs can differentiate into neural cells and induce motor function improvement in the cord injured rat models. Especially, the BDNF has effectiveness for neurological function improvement due to axonal regeneration in the early cord injury stage. Thus the HUCBs and BDNF have recovery effects of a moderate degree for cord injured rats.     

Social and environmental enrichment improves sensory and motor recovery after severe contusive spinal cord injury in the rat

Neuropathic pain and motor dysfunction are difficult problems following spinal cord injury (SCI). Social and environmental enrichment (SEE), which models much of the clinical rehabilitation environment for post-SCI persons, is the focus of the current investigation which examines the effects of multiple-housing and the addition of climbing spaces, improved bedding and crawl toys on the sensory and motor recovery following a severe contusive SCI. Efficacy was determined with sensory testing, open-field motor behavioral testing, lesion volume analysis and quantification of brain-derived neurotrophic factor (BDNF) in the lumbar spinal cord with and without SEE provided during the recovery period. Sensory and motor testing were performed weekly for 12 weeks following SCI. SEE significantly and permanently reversed cutaneous allodynia, but not thermal hyperalgesia, to near normal levels. The gross locomotor performance (BBB [Basso, Beattie, and Bresnahan] motor scores) significantly improved about two points. In addition, the BBB subscale scores were significantly improved nearly seven points by the end of the study. SEE also significantly improved foot rotation to normal levels and reduced gridwalk footfall errors nearly 50%, but had no effect on stride length or base of support dysfunctions. SEE significantly increased the total volume of a thoracic segment of cord encompassing the injury site at 12 weeks, by reducing cavitation and increasing both the volume of grey and white matter spared, compared to SCI alone. When BDNF levels were examined in the injured lumbar spinal cord, SEE significantly returned BDNF levels to near-normal. These data suggest that immediate use of SEE after contusive SCI is able to improve overall spinal cell survival and prevent much of the sensory and motor dysfunction that accompanies contusive SCI.     

Brain-derived neurotrophic factor suppresses delayed apoptosis of oligodendrocytes after spinal cord injury in rats

We evaluated the effect of brain-derived neurotrophic factor (BDNF) on cell death after spinal cord injury. A rat spinal cord injury model was produced by static load, and continuous intrathecal BDNF or vehicle infusion was carried out either immediately or 3 days after the injury. Cell death was examined by nuclear staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). After injury, typical apoptotic cells were observed. Double staining with TUNEL and specific cell markers revealed that, soon after the injury, the apoptotic or necrotic cells at the injury site were neurons and microglia. One week after the injury, apoptotic oligodendrocytes, but not apoptotic astrocytes, were observed in the white matter rostral and caudal to the injury site, whereas few apoptotic cells were found in the gray matter. The immediate BDNF treatment significantly reduced the number of TUNEL-positive cells in the adjacent rostral site 1 and 2 weeks after the injury, and in the adjacent caudal site 3 days and 1 week after the injury, even though there was no significant difference between BDNF-treated and control rats at the injury site itself. In addition, similar antiapoptotic effects were observed in these regions 1 week after injury in rats that received BDNF treatment from the third day after injury. These findings suggest that BDNF suppresses delayed apoptosis of oligodendrocytes after spinal cord injury, for which even delayed injections are effective. BDNF administration may therefore be useful for the clinical treatment of spinal cord injury through the suppression of secondary events.     

Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury

Activity-based therapies such as passive bicycling and step-training on a treadmill contribute to motor recovery after spinal cord injury (SCI), leading to a greater number of steps performed, improved gait kinematics, recovery of phase-dependent modulation of spinal reflexes, and prevention of decrease in muscle mass. Both tasks consist of alternating movements that rhythmically stretch and shorten hindlimb muscles. However, the paralyzed hindlimbs are passively moved by a motorized apparatus during bike-training, whereas locomotor movements during step-training are generated by spinal networks triggered by afferent feedback. Our objective was to compare the task-dependent effect of bike- and step-training after SCI on physiological measures of spinal cord plasticity in relation to changes in levels of neurotrophic factors. Thirty adult female Sprague-Dawley rats underwent complete spinal transection at a low thoracic level (T12). The rats were assigned to one of three groups: bike-training, step-training, or no training. The exercise regimen consisted of 15?min/d, 5 days/week, for 4 weeks, beginning 5 days after SCI. During a terminal experiment, H-reflexes were recorded from interosseus foot muscles following stimulation of the tibial nerve at 0.3, 5, or 10?Hz. The animals were sacrificed and the spinal cords were harvested for Western blot analysis of the expression of neurotrophic factors in the lumbar spinal cord. We provide evidence that bike- and step-training significantly increase the levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4 in the lumbar enlargement of SCI rats, whereas only step-training increased glial cell-derived neurotrophic factor (GDNF) levels. An increase in neurotrophic factor protein levels that positively correlated with the recovery of H-reflex frequency-dependent depression suggests a role for neurotrophic factors in reflex normalization.     

Cellular localization of tumor necrosis factor-alpha following acute spinal cord injury in adult rats

Posttraumatic inflammatory reaction may contribute to secondary injury after traumatic spinal cord injury (SCI). Expression of tumor necrosis factor-alpha (TNF-alpha), a key inflammatory mediator, has been demonstrated in the injured cord. However, the specific cell types that are responsible for TNF-alpha expression after SCI remain to be identified. In the present study, cellular sources of TNF-alpha were examined in rats that received a spinal cord impact injury at the 9th thoracic (T9) level. Here we demonstrate that, within hours after SCI, increased TNF-alpha immunoreactivity was localized in neurons, glial cells (including astrocytes, oligodendrocytes, and microglia), and endothelial cells in areas of the spinal cord adjacent to the lesion site. Myelin breakdown was noted in oligodendrocytes that are immunopositive for TNF-alpha. In sham-operated controls, a low level of TNF-alpha immunoreactivity was detected. In antigen-absorption experiments, no TNF-alpha immunoreactivity was detected, indicating the specificity of TNF-alpha immunocytochemistry in the present study. Results suggest that various cell types, including neurons, glial cells, and vascular endothelial cells, contribute to TNF-alpha production in the injured cord.     

Rescue of rat anterior horn neurons after spinal cord injury by retrograde transfection of adenovirus vector carrying brain-derived neurotrophic factor gene

We investigated the efficacy of retrograde gene delivery via the sternomastoid muscle of recombinant adenovirus vector (AdV) carrying brain-derived neurotrophic factor (BDNF) gene for the rescue of injured rat spinal cord. One hundred-thirty five adult Sprague-Dawley rats were used in the study with a standard weight-compression technique to produce spinal cord injury. AdV-BDNF gene or AdV-beta-galactosidase (AdV-LacZ) gene was injected into the sternomastoid muscle immediately after traumatic C4 segment spinal cord injury. AdV-BDNF was successfully appeared in the injured cervical spinal cord following injection into the sternomastoid muscle. BDNF expression in the anterior horn neurons of the cervical spinal cord reached peak levels at 1-2 weeks; and the expression persisted at significant levels for approximately 4 weeks after injury. AdV-BDNF transfection was associated with increased numbers of intact neurons as confirmed by Nissl, cholineacetyltransferase (ChAT), and acetylcholine esterase (AChE) staining especially from 2 weeks after injury, compared with the AdV-LacZ injected rats. Our results suggest that in vivo targeted retrograde AdV-BDNF-gene delivery may enhance neuronal survival following traumatic injury of the spinal cord.     

Effect of fetal spinal cord graft with different methods on axonal pathology after spinal cord contusion

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成年脊髓损伤大鼠脊髓神经干细胞的体外培养及分化研究

目的 探讨大鼠脊髓损伤后脊髓神经干细胞的分离培养方法及分化情况.方法 采用Allen法制作大鼠脊髓损伤模型,利用无血清培养和单细胞克隆技术在成年脊髓损伤7 d大鼠脊髓中分离具有单细胞克隆能力的神经干细胞,并进行培养鉴定.结果 从成年脊髓损伤7 d大鼠脊髓中成功分离出神经干细胞,该细胞具有连续克隆能力,可传代培养,表达神经巢蛋白抗原.分化后的细胞表达神经元细胞、星形胶质细胞和少突胶质细胞的特异性抗原.结论 致伤7 d的成年大鼠脊髓组织体外町培养出神经十细胞,并分化为神经无细胞、星形胶质细胞和少突胶质细胞,有可能参与脊髓损伤的修复过程.     

Dissociated predegenerated peripheral nerve transplants for spinal cord injury repair: a comprehensive assessment of their effects on regeneration and functional recovery compared to schwann cell transplants

Abstract Several recent studies suggest that predegenerated nerves (PDNs) or dissociated PDNs (dPDNs) can improve behavioral and histological outcomes following transplantation into the injured rat spinal cord. In the current study we tested the efficacy of dPDN transplantation by grafting cells isolated from the sciatic nerve 7 days after crush. We did not replicate one study, but rather assessed what appeared, based on five published reports, to be a reported robust effect of dPDN grafts on corticospinal tract (CST) regeneration and locomotor recovery. Using a standardized rodent spinal cord injury model (200 kD IH contusion) and transplantation procedure (injection of GFP(+) cells 7 days post-SCI), we demonstrate that dPDN grafts survive within the injured spinal cord and promote the ingrowth of axons to a similar extent as purified Schwann cell (SC) grafts. We also demonstrate for the first time that while both dPDN and SC grafts promote the ingrowth of CGRP axons, neither graft results in mechanical or thermal hyperalgesia. Unlike previous studies, dPDN grafts did not promote long-distance axonal growth of CST axons, brainstem spinal axons, or ascending dorsal column sensory axons. Moreover, using a battery of locomotor tests (Basso Beattie Bresnahan [BBB] score, BBB subscore, inked footprint, Catwalk, and ladderwalk), we failed to detect any beneficial effects of dPDN transplantation on the recovery of locomotor function after SCI. We conclude that dPDN transplants are not sufficient to promote CST regeneration or locomotor recovery after SCI.     

Amiloride improves locomotor recovery after spinal cord injury

Amiloride is a drug approved by the United States Food and Drug Administration, which has shown neuroprotective effects in different neuropathological conditions, including brain injury or brain ischemia, but has not been tested in spinal cord injury (SCI). We tested amiloride's therapeutic potential in a clinically relevant rat model of contusion SCI inflicted at the thoracic segment T10. Rats receiving daily administration of amiloride from 24?h to 35 days after SCI exhibited a significant improvement in hindlimb locomotor ability at 21, 28, and 35 days after injury, when compared to vehicle-treated SCI rats. Rats receiving amiloride treatment also exhibited a significant increase in myelin oligodendrocyte glycoprotein (MOG) levels 35 days after SCI at the site of injury (T10) when compared to vehicle-treated controls, which indicated a partial reverse in the decrease of MOG observed with injury. Our data indicate that higher levels of MOG correlate with improved locomotor recovery after SCI, and that this may explain the beneficial effects of amiloride after SCI. Given that amiloride treatment after SCI caused a significant preservation of myelin levels, and improved locomotor recovery, it should be considered as a possible therapeutic intervention after SCI.     

Effect of human neural progenitor cells on injured spinal cord

Human central nervous system ( CNS) has verylimited regenerative potentials. Patients withsevere injuries in the CNS such as spinal cordinjury (SCI) frequently endure lifelong disability. Avariety of methods have been tried to prevent spinalcord from further injury and foster regeneration afterSCI. Despite these efforts, an effective treatment forthis disease is still lacking. Since neural progenitorcells have already committed to become neural cells inthe CNS, they appear to be a good c…     

Neuronal populations capable of regeneration following a combined treatment in rats with spinal cord transection

Axonal regeneration after spinal cord injury (SCI) in adult mammals is limited by inhibitors associated with myelin and the glial scar. To overcome these inhibitors, a combined approach will be required. We have previously demonstrated that, following complete SCI in rats, a combination of bridging the lesion with Schwann cell (SC)-filled guidance channels, olfactory ensheathing glia implantation, and chondroitinase ABC delivery promoted regeneration of serotonergic fibers into the lumbar spinal cord. In addition, this combined treatment significantly improved locomotor recovery. To complement these findings, we repeated this combined treatment to assess whether fibers other than serotonergic axons were able to regenerate into the caudal spinal cord. In this experiment, we injected the retrograde tracer FluoroGold (FG) into the spinal cord caudal to a complete transection in a control and a treated group. FG-positive cells rostral to the lesion and in the brainstem of animals in the treated group showed that axons were able to regenerate across the SC bridge and into the caudal spinal cord. Treated rats had labeled cells in the reticulospinal nuclei, vestibular nuclei, and the raphe nucleus as well as in the spinal cord. Cell numbers were highest in the thoracic spinal cord and the lateral vestibular nucleus. Determining the mechanisms for the superior capability of these cell populations to regenerate may provide valuable clues in the design of future treatment approaches.