Biomaterials reinforced MSCs transplantation for spinal cord injury repair

Due to the complex pathophysiological mechanism, spinal cord injury (SCI) has become one of the most intractable central nervous system (CNS) diseases to therapy. Stem cell transplantation, mesenchymal stem cells (MSCs) particularly, appeals to more and more attention along with the encouraging therapeutic results for the functional regeneration of SCI. However, traditional cell transplantation strategies have some limitations, including the unsatisfying survival rate of MSCs and their random di...     

Neuroprotection and regeneration strategies for spinal cord repair

The journey toward a cure for spinal cord injury (SCI) has taken many paths. In this article, we review these paths, and highlight the clinical applications of these experimental repair strategies. Initial strategies involved attempts at neuroprotection with steroids and other anti-inflammatory drugs. Other anti-ischemia treatments, agents to eliminate the damage from excitotoxicity, and anti-apoptotic agents were also tried. Another avenue involved enhancing the function of the remaining uninjured axons by measures to produce remyelination and medications to improve axonal conduction. In the last two decades there has been a major effort to enhance spinal cord axonal regeneration through a variety of techniques including neutralization of neurite inhibition, administration of neurotrophic factors, implantation of synthetic channels, and transplantation of a variety of cell types. Indeed, several of these strategies have been so promising in animals that clinicians have been stimulated to explore their potential human application. We also examine the different experimental models of SCI used to assess repair, and discuss how the injury model impacts on the assessment of axonal regeneration and functional recovery after SCI. The mechanisms of recovery that may be involved after SCI will be analyzed, and their relevance toward finding a cure for human SCI. Unfortunately, the goal of producing significant functional regeneration of the human spinal cord has not yet been achieved despite the many strategies that have been developed. It is our hope that improved understanding of the mechanisms underlying functional recovery will lead to successful therapeutic strategies in humans.     

Cytokine transport across the injured blood-spinal cord barrier

Spinal cord injury (SCI) induces dynamic changes of the blood-spinal cord barrier and even the more distant blood-brain barrier. Besides an immediate increase of paracellular permeability resulting from the direct impact of the injury, the transport systems for selective cytokines undergo regulatory changes. Since many of the transported molecules play essential roles in neuroregeneration, we propose that this altered peripheral tissue / CNS interaction benefits remodeling of the spinal cord and functional recovery after SCI. This review examines the transport of cytokines and neurotrophic factors into the spinal cord, emphasizing the upregulation of two cytokines--tumor necrosis factor alpha (TNF) and leukemia inhibitory factor (LIF)--during the course of SCI. The increased transport of TNF and LIF after SCI remains saturable and does not coincide with generalized BBB disruption, highlighting a pivotal regulatory role for the blood-spinal cord barrier.     

移植维甲酸诱导的人胚神经干细胞在受损大鼠脊髓内的分化及作用

目的 将维甲酸(RA)诱导的人胚神经干细胞移植入受损的大鼠脊髓内，观察大鼠后肢运动功能的变化及细胞的分化情况。方法 实验大鼠30只遭受脊髓中度损伤后7天作移植治疗，实验组分两组：一组移植经维甲酸诱导后的细胞，另一组移植未诱导的细胞；对照组注射等量PBS液。每周一次观察大鼠后肢运动情况，移植后4周，应用免疫组化技术检测移植细胞在大鼠脊髓内的生存和分化情况。结果 实验组大鼠脊髓内见许多移植细胞存在，部分可分化出神经元样细胞，其后肢运动功能优于对照组。其中维甲酸诱导组能分化出神经元样细胞，其促进脊髓功能恢复的能力较另一组更强。结论 维甲酸预处理的神经干细胞在体内能替代缺失的神经细胞，促进受损的脊髓功能恢复．在脊髓损伤的临床治疗中具有潜在的应用价值。     

Fasudil促进大鼠损伤脊髓神经功能恢复的研究

目的研究Rho激酶抑制剂Fasudil对大鼠脊髓损伤的促修复作用。方法用健康成年SD大鼠建立脊髓损伤模型,通过腹腔注射盐酸法舒地尔,并设立对照。术后1、2、4周,运用BBB功能评分进行后肢运动功能评价;损伤后4周,脊髓损伤局部行SABC法ROCK2免疫组织化学染色。结果术后1、2、4周,Fasudil治疗组与对照组比较,评分明显增高(P<0.05);术后4周Fasudil治疗组损伤局部组织内ROCK2的表达较对照组明显减少(P<0.05)。结论腹腔注射Fasudil能够减少脊髓损伤局部ROCK2表达,改善大鼠的运动功能。     

Loss of hsp70.1 Decreases Functional Motor Recovery after Spinal Cord Injury in Mice

Heat shock proteins (HSPs) are specifically induced by various forms of stress. Hsp70.1, a member of the hsp70 family is known to play an important role in cytoprotection from stressful insults. However, the functional role of Hsp70 in motor function after spinal cord injury (SCI) is still unclear. To study the role of hsp70.1 in motor recovery following SCI, we assessed locomotor function in hsp70.1 knockout (KO) mice and their wild-type (WT) mice via the Basso, Beattie and Bresnahan (BBB) locomotor rating scale, before and after spinal hemisection at T13 level. We also examined lesion size in the spinal cord using Luxol fast blue/cresyl violet staining. One day after injury, KO and WT mice showed no significant difference in the motor function due to complete paralysis following spinal hemisection. However, when it compared to WT mice, KO mice had significantly delayed and decreased functional outcomes from 4 days up to 21 days after SCI. KO mice also showed significantly greater lesion size in the spinal cord than WT mice showed at 21 days after spinal hemisection. These results suggest that Hsp70 has a protective effect against traumatic SCI and the manipulation of the hsp70.1 gene may help improve the recovery of motor function, thereby enhancing neuroprotection after SCI.     

Salvianolic acid B promotes survival of transplanted mesenchymal stem cells in spinal cord-injured rats

AIM: Stem cells hold great promise for brain and spinal cord injuries (SCI), but cell survival following transplantation to adult central nervous system has been poor. Salvianolic acid B (Sal B) has been shown to improve functional recovery in brain-injured rats. The present study was designed to determine whether Sal B could improve transplanted mesenchymal stem cell (MSC) survival in SCI rats. METHODS: SCI rats were treated with Sal B. The Basso-Beatie-Bresnahan (BBB) scale was used to test the functional recovery. Sal B was used to protect MSC from being damaged by TNF-alpha in vitro. Bromodeoxyuridine-labeled MSC were transplanted into SCI rats with Sal B intraperitoneal injection, simultaneously. MSC were examined, and the functional recovery of the SCI rats was tested. RESULTS: Sal B treatment significantly reduced the lesion area from 0.26+/-0.05 mm2 to 0.15+/-0.03 mm2 (P<0.01) and remarkably raised the BBB scores on d 28, post-injury, from 7.3+/-0.9 to 10.5+/-1.3 (P<0.05), compared with the phosphate-buffered saline (PBS) control group. MSC were protected from the damage of TNF-alpha by Sal B. The number of surviving MSC in the MSC plus Sal B groups were 1143.3+/-195.6 and 764.0+/-81.3 on d 7 and 28, post-transplantation, more than those in the MSC group, which was 569.3+/-72.3 and 237.0+/-61.3, respectively (P<0.05). Rats with MSC transplanted and Sal B injected obtained higher BBB scores than those with MSC transplanted alone (P<0.05) and PBS (P<0.01). CONCLUSION: Sal B provides neuroprotection to SCI and promotes the survival of MSC in vitro and after cell transplantation to the injured spinal cord in vivo.     

Repetitive Treatment with Diluted Bee Venom Attenuates the Induction of Below-Level Neuropathic Pain Behaviors in a Rat Spinal Cord Injury Model

The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to examine the potential anti-nociceptive effect of repetitive DBV treatment in the development of below-level neuropathic pain in spinal cord injury (SCI) rats. DBV was applied into the Joksamli acupoint during the induction and maintenance phase following thoracic 13 (T13) spinal hemisection. We examined the effect of repetitive DBV stimulation on SCI-induced bilateral pain behaviors, glia expression and motor function recovery. Repetitive DBV stimulation during the induction period, but not the maintenance, suppressed pain behavior in the ipsilateral hind paw. Moreover, SCI-induced increase in spinal glia expression was also suppressed by repetitive DBV treatment in the ipsilateral dorsal spinal cord. Finally, DBV injection facilitated motor function recovery as indicated by the Basso–Beattie–Bresnahan rating score. These results indicate that the repetitive application of DBV during the induction phase not only decreased neuropathic pain behavior and glia expression, but also enhanced locomotor functional recovery after SCI. This study suggests that DBV acupuncture can be a potential clinical therapy for SCI management.     

大鼠胚胎神经干细胞异体移植对脊髓损伤的修复

目的 观察胚胎神经干细胞(neural stem cells,NSCs)对成年大鼠脊髓损伤(spianl cord injury,SCI)的修复及对轴突再生的作用.方法 制作20只大鼠SCI(T7)模型,随机分为实验组和对照组.伤后2 d实验组移植经全离培养的Wistar大鼠NSCs;对照组只注入DMEM培养液.移植后第1、2、4、6周经电镜及免疫组化观察移植对脊髓轴突再生的影响.结果 实验组NSCs与宿主融合较好,损伤区可见幼稚的呈束状排列的再生轴突;对照组轴突变性未见再生轴突.结论 NSCs植入异体大鼠打击伤后的脊髓可存活,并产生髓鞘样物质促进宿主脊髓轴突再生.     

Rethinking the clinical management of volumetric muscle loss in patients with spinal cord injury: Synergy among nutritional supplementation,pharmacotherapy, and rehabilitation

Spinal cord injury (SCI) is a condition defining the damage of the spinal cord that leads to musculoskeletal sequelae, including volumetric muscle loss (VML) in a significant proportion of patients. VML occurring after SCI is responsible for delayed recovery, with detrimental consequences in terms of functional outcomes and additional alterations of the muscle tissue. The treatment of muscle alterations in these patients usually relies on nutritional supplementation. However, rehabilitation therapy has a well-recognized role in improving muscle mass and function, even in subjects affected by SCI. Furthermore, novel medical therapies have been recently investigated, with positive results. In this scoping review, we portray the state-of-the-art treatment of muscle modifications after SCI, focusing on the multidisciplinary and multidimensional management of these patients.     

Schwann cell transplantation for CNS repair

Demyelination occurs in several central nervous system (CNS) disorders, including multiple sclerosis, viral infection and spinal cord injury and can result in severe functional impairment. Therefore there is great interest in developing therapies promoting repair in CNS demyelinating diseases and trauma. Cell replacement therapy is an attractive approach for myelin repair, and experimental transplantation has provided convincing evidence of the repair potential of grafted myelin-forming cells. Schwann cells (SCs), oligodendrocyte progenitors, olfactory ensheathing cells and embryonic and neural stem cells have been shown to form myelin after transplantation into the demyelinated CNS. SCs are among the most promising candidates for autologous grafting. They can remyelinate spinal cord lesions after experimental demyelination, leading in some cases to functional recovery in rodent and primate models. However, SCs do not normally enter the CNS, and migration of SCs transplanted in CNS white matter is inhibited by astrocytes. As SC migration and myelination is mediated by interactions of sets of extracellular matrix molecules with cell surface molecules, genetic engineering of SCs to alter aspects of these interactions is a possible way forward. Thus efforts towards the development of SC-based therapies are focused in enhancing their migration and functional integration into the lesioned CNS. In addition, efforts are being made to use these cells as gene delivery vehicles for an array of molecules with repair potential. In this review we summarize data from the recent literature regarding the use of SCs in CNS repair and discuss the prospects for future therapeutic applications.     

Neural plasticity after spinal cord injury

Spinal cord injury (SCI) has devastating physical and socioeconomical impact. However, some degree of functional recovery is frequently observed in patients after SCI. There is considerable evidence that functional plasticity occurs in cerebral cortical maps of the body, which may account for functional recovery after injury. Additionally, these plasticity changes also occur at multiple levels including the brainstem, spinal cord, and peripheral nervous system. Although the interaction of plasticity changes at each level has been less well studied, it is likely that changes in subcortical levels contribute to cortical reorganization. Since the permeability of the blood-brain barrier (BBB) is changed, SCI-induced factors, such as cytokines and growth factors, can be involved in the plasticity events, thus affecting the final functional recovery after SCI. The mechanism of plasticity probably differs depending on the time frame. The reorganization that is rapidly induced by acute injury is likely based on unmasking of latent synapses resulting from modulation of neurotransmitters, while the long-term changes after chronic injury involve changes of synaptic efficacy modulated by long-term potentiation and axonal regeneration and sprouting. The functional significance of neural plasticity after SCI remains unclear. It indicates that in some situations plasticity changes can result in functional improvement, while in other situations they may have harmful consequences. Thus, further understanding of the mechanisms of plasticity could lead to better ways of promoting useful reorganization and preventing undesirable consequences.     

大鼠T7脊髓半横切损伤模型的建立及饲养护理

目的制备SD大鼠T7脊髓半横切动物模型,模拟脊髓损伤,为后期治疗脊髓损伤研究提供实验数据。方法24只健康SD大鼠随机分为对照组及脊髓损伤组,每组12只。SCI组咬除T6～8棘突及相应椎板,暴露相应脊髓,定量切除T7右半侧脊髓组织;对照组仅切除相应椎板。术后行人工排尿、排便等护理,于3d、7d分别进行BBB运动功能评分及感觉诱发电位（sensory evoked potentials,SEP）检测,并取T7脊髓行组织学观察。结果SCI组所有动物在术后均表现出典型的脊髓半切症状;BBB运动功能评分低于8分;术后3d及7d损伤组检测不到SEP,而对照组潜伏期轻度延长及波幅轻度下降;脊髓形态学观察显示该方法达到脊髓半横切要求;术后SCI组大鼠无死亡。结论大鼠T7脊髓半横切损伤模型建立成功,有效的术后护理可提高模型大鼠的生存率。     

脊髓损伤患者膀胱功能康复训练及效果分析

目的:探讨早期训练对脊髓损伤患者膀胱功能康复疗效．方法:采用各种刺激使脊髓低级排尿中枢引起反射性尿道外括约肌协同松驰这一原理,综合设定有效的耐力训练、定时的手法按摩及夹闭尿管定时放尿的方法进行早期膀胱功能训练,促进反射性膀胱功能的形成。结果:76例患者中67例(88．16％)在2—3周内建立反射性膀胱功能,达到优良标准。膀胱训练后,残余尿测定成功率达89．47％,泌尿系统感染下降率为87．5％。出院1年后跟踪观察均能顺利排尿。结论:有效的耐力训练与定时的手法按摩是脊髓损伤患者膀胱功能早期康复的有效方法。值得临床推广应用.     

The role of propriospinal interneurons in recovery from spinal cord injury

Over one hundred years ago, Sir Charles Sherrington described a population of spinal cord interneurons (INs) that connect multiple spinal cord segments and participate in complex or ‘long’ motor reflexes. These neurons were subsequently termed propriospinal neurons (PNs) and are known to play a crucial role in motor control and sensory processing. Recent work has shown that PNs may also be an important substrate for recovery from spinal cord injury (SCI) as they contribute to plastic reorganisation of spinal circuits. The location, inter-segmental projection pattern and sheer number of PNs mean that after SCI, a significant number of them are capable of ‘bridging’ an incomplete spinal cord lesion. When these properties are combined with the capacity of PNs to activate and coordinate locomotor central pattern generators (CPGs), it is clear they are ideally placed to assist locomotor recovery. Here we summarise the anatomy, organisation and function of PNs in the uninjured spinal cord, briefly outline the pathophysiology of SCI, describe how PNs contribute to recovery of motor function, and finally, we discuss the mechanisms that underlie PN plasticity. We propose there are two major challenges for PN research. The first is to learn more about ways we can promote PN plasticity and manipulate the ‘hostile’ micro-environment that limits regeneration in the damaged spinal cord. The second is to study the cellular/intrinsic properties of PNs to better understand their function in both the normal and injured spinal cord.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

Effects of Human Mesenchymal Stem Cell Transplantation Combined with Polymer on Functional Recovery Following Spinal Cord Hemisection in Rats

The spontaneous axon regeneration of damaged neurons is limited after spinal cord injury (SCI). Recently, mesenchymal stem cell (MSC) transplantation was proposed as a potential approach for enhancing nerve regeneration that avoids the ethical issues associated with embryonic stem cell transplantation. As SCI is a complex pathological entity, the treatment of SCI requires a multipronged approach. The purpose of the present study was to investigate the functional recovery and therapeutic potential of human MSCs (hMSCs) and polymer in a spinal cord hemisection injury model. Rats were subjected to hemisection injuries and then divided into three groups. Two groups of rats underwent partial thoracic hemisection injury followed by implantation of either polymer only or polymer with hMSCs. Another hemisection-only group was used as a control. Behavioral, electrophysiological and immunohistochemical studies were performed on all rats. The functional recovery was significantly improved in the polymer with hMSC-transplanted group as compared with control at five weeks after transplantation. The results of electrophysiologic study demonstrated that the latency of somatosensory-evoked potentials (SSEPs) in the polymer with hMSC-transplanted group was significantly shorter than in the hemisection-only control group. In the results of immunohistochemical study, β-gal-positive cells were observed in the injured and adjacent sites after hMSC transplantation. Surviving hMSCs differentiated into various cell types such as neurons, astrocytes and oligodendrocytes. These data suggest that hMSC transplantation with polymer may play an important role in functional recovery and axonal regeneration after SCI, and may be a potential therapeutic strategy for SCI.     

Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages

INTRODUCTION: Macrophage activation is a hallmark of spinal cord injury (SCI) pathology. CNS macrophages, derived from resident microglia and blood monocytes, are ubiquitous throughout the injured spinal cord, and respond to signals in the lesion environment by changing their phenotype and function. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair. AREAS COVERED: This review provides a comprehensive overview of current SCI clinical trials that are intended to promote neuroprotection, axon regeneration or cell replacement. None of these potential therapies were developed with the goal of influencing macrophage function; however, it is likely that each will have direct or indirect effects on CNS macrophages. The potential impact of each trial is discussed in the context of CNS macrophage biology. EXPERT OPINION: Activation of CNS macrophages is an inevitable consequence of traumatic SCI. Given that these cells are exquisitely sensitive to changes in microenvironment, any intervention that affects tissue integrity and/or the composition of the cellular milieu will undoubtedly affect CNS macrophages. Thus, it is important to understand how current clinical trials will affect intrinsic CNS macrophages.     

New perspectives for the treatment options in spinal cord injury

Spinal cord injury (SCI) is a serious clinical disorder that leads to lifetime disability for which no suitable therapeutic agents are available so far. Further research is needed to understand the basic mechanisms of spinal cord pathology that results in permanent disability and poses a heavy burden on our society. In the past, a lot of effort was placed on improving functional outcome with the help of various therapeutic agents, however less attention has been paid on the development and propagation of spinal cord pathology over time. Thus, it is still unclear whether improvement of functional outcome is related to spinal cord pathology or vice versa. Few drugs are able to influence functional outcome without having any improvement on cord pathology. Some drugs, however, can lessen cord pathology but fail to influence the functional outcome. The goal of future treatment options for SCI is therefore to find suitable new drugs or a combination of existing drugs and to use various cellular transplants, neurotrophic factors, myelin-inhibiting factors, tissue engineering and nano-drug delivery to improve both the functional and the pathological outcome in the inured patient. This review deals with the key aspects of the latest treatments for SCI and suggests some possible future therapeutic measures to enhance healthcare in clinical situations.     

New perspectives for the treatment options in spinal cord injury

Spinal cord injury (SCI) is a serious clinical disorder that leads to lifetime disability for which no suitable therapeutic agents are available so far. Further research is needed to understand the basic mechanisms of spinal cord pathology that results in permanent disability and poses a heavy burden on our society. In the past, a lot of effort was placed on improving functional outcome with the help of various therapeutic agents, however less attention has been paid on the development and propagation of spinal cord pathology over time. Thus, it is still unclear whether improvement of functional outcome is related to spinal cord pathology or vice versa. Few drugs are able to influence functional outcome without having any improvement on cord pathology. Some drugs, however, can lessen cord pathology but fail to influence the functional outcome. The goal of future treatment options for SCI is therefore to find suitable new drugs or a combination of existing drugs and to use various cellular transplants, neurotrophic factors, myelin-inhibiting factors, tissue engineering and nano-drug delivery to improve both the functional and the pathological outcome in the inured patient. This review deals with the key aspects of the latest treatments for SCI and suggests some possible future therapeutic measures to enhance healthcare in clinical situations.     

骨髓间充质干细胞移植促进脊髓神经功能修复机制的研究

目的:观察骨髓间充质干细胞(BMSC)移植对脊髓损伤后神经功能恢复、星形胶质细胞增生、空洞形成以及神经细胞凋亡的影响.方法:提取BMSC,制作SD大鼠脊髓损伤模型80只,随机分为埘照组(A组)和细胞移植组(B组).1周后再次手术,用微量注射器刺人B组脊髓损伤部位两端,分别缓慢推入10 μL BMSC悬液,A组注入等量PBS,于移植后1、2、4、6、8周观察神经恢复情况;移植后第1、2、3、7、14天行TUNEL染色和电镜检查观察神经细胞凋亡情况.8周后行胶质纤维酸性蛋白(GFAP)及神经生长抑制因子Nogo-A免疫组化,测量各组脊髓空洞的大小.结果:8周后A组和B组神经功能评估(BBB评分)分别为(22.0±2.1)分和(28.5±2.7)分,14 d时凋亡细胞数分别为14.4±2.7和9.1±3.3;白质中GFAP阳性细胞数分别为32.3±1.3和23.7±0.6,Nogo-A阳性神经元分别为(108.6±125.8)个和(78.3±12.4)个,空洞体积分别为(23.3±12.4)mm3和(14.5±10.6)mm3,2组间比较差别均有统计学意义(P＜0.05).结论:骨髓间充质干细胞可通过减少星形胶质细胞的增生,缩小空洞,抑制Nogo-A以及神经细胞凋亡等机制促进脊髓神经功能的恢复.