Tubular conduits,cell-based therapy and exercise to improve peripheral nerve regeneration

Peripheral nerve injuries （PNI） are a major clinical prob- lem. In general, PNI results from motor vehicle accidents, lacerations with sharp objects, penetrating trauma （gunshot wounds） and stretching or crushing trauma and fractures. It is estimated that PNI occur in 2.8% of trauma patients and this number reaches 5% if plexus and root lesions are in- cluded. However, due to lack of recent epidemiological stud- ies, these data probably underestimate the actual number of nerve injuries

Angiogenesis and nerve regeneration induced by local administration of plasmid pBud-coVEGF165-coFGF2 into the intact rat sciatic nerve

Vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present study, we elucidated the local and systemic effects of plasmid construct рBud-coVEGF165-coFGF2 injected into the epineurium of intact rat sciatic nerve. Results of histological examination of sciatic nerve and multiplex immunoassays of serum showed the absence of immunogenicity and biosafety of plasmid рBud-coVEGF165-coFGF2. Moreover, local administration of plasmid DNA construct resulted in significantly decreased levels of pro-inflammatory cytokines in the peripheral blood, including tumor necrosis factor α(TNFα) and interleukin-12, and significantly increased levels of cytokines and chemokines including Regulated upon Activation, Normal T Cell Expressed and Presumably Secrete(RANTES), epidermal growth factor, interleukin-2, and monocyte chemoattractant protein 1. These changes in the peripheral blood on day 7 after injection of plasmid construct рBud-coVEGF165-coFGF2 show that the plasmid construct has systemic effects and may modulate immune response. At the same time, reverse transcriptionpolymerase chain reaction revealed transient expression of coFGF2, coVEGF165, ratFGF2 and ratVEGFA with direct transport of transcripts from distal part to proximal part of the sciatic nerve. Immunohistochemical staining revealed prolonged presence of VEGFA in sciatic nerve till 14 days post-injection. These findings suggest that local administration of plasmid construct рBud-coVEGF165-coFGF2 at a concentration of 30 ng/μL results in the formation of pro-angiogenic stimuli and, and the plasmid construct, used as a drug for gene therapy, might potentially facilitate regeneration of the sciatic nerve. The study was approved by the Animal Ethics Committee of Kazan Federal University, procedures were approved by the Local Ethics Committee(approval No. 5) on May 27, 2014.

Adipose derived stem cells and nerve regeneration

Injuries to peripheral nerves are common and cause life-changing problems for patients alongside high social and health care costs for society. Current clinical treatment of peripheral nerve injuries predominantly relies on sacrificing a section of nerve from elsewhere in the body to provide a graft at the injury site. Much work has been done to develop a bioengineered nerve graft, precluding sacrifice of a functional nerve. Stem cells are prime candidates as accelerators of regeneration in these nerve grafts. This review examines the potential of adipose-derived stem cells to improve nerve repair assisted by bioengineered nerve grafts.

Therapeutic approaches enhancing peripheral nerve regeneration

Peripheral nerve injury is a common occurrence and represents a major economic burden for society. The development of novel strategies to enhance peripheral nerve regeneration is, therefore, of great relevance. Conventional treatments include surgical repair of the damaged nerves for minor injuries, whereas autologous nerve grafts are required to recover longer interruptions. However, despite great surgical advances, functional recovery is often poor. Although it is well known that the peripheral nervous system has a greater regenerative capacity than the central nervous system and, considering the scientific advancements and knowledge in regenerative medicine, clinical applications appears still limited. This review provides an overview of the methodological approaches currently under study, aimed at enhancing peripheral nerve regeneration. In particular, tissue engineering, cell therapy and pharmacological approaches will be discussed.

Modified insulin-like growth factor 1 containing collagen-binding domain for nerve regeneration

Insulin-like growth factor 1 （IGF-I） is a potential nutrient for nerve repair. However, it is impractical as a therapy because of its limited half- life, rapid clearance, and limited target specificity. To achieve targeted and long-lasting treatment, we investigated the addition of a binding structure by fusing a collagen-binding domain to IGF- 1. After confirming its affinity for collagen, the biological activity of this construct was examined by measuring cell proliferation after transfection into PC12 and Schwann cells using a 3-（4,5-dimethyl-2-thiazolyl）-2,5-di- phenyl-2-H-tetrazolium bromide assay. Immunofluorescence staining was conducted to detect neurofilament and microtubule-associated protein 2 expression, while real time-polymerase chain reaction was utilized to determine IGF-1 receptor and nerve growth/actor mRNA expression. Our results demonstrate a significant increase in collagen-binding activity of the recombinant protein compared with IGF-1. Moreover, the recombinant protein promoted proliferation of PC12 and Schwann cells, and increased the expression of neurofilament and microtubule-associated protein 2. Importantly, the recombinant protein also stimulated sustained expression of IGF-1 receptor and nerve growth factor mRNA for days. These results show that the recombinant protein achieved the goal of targeting and long-lasting treatment, and thus could become a clinically used factor for promoting nerve regeneration with a prolonged therapeutic effect.

PTEN knockdown with the Y444F mutant AAV2 vector promotes axonal regeneration in the adult optic nerve

The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3K/AKT/mTOR signaling pathway has been shown to enhance the intrinsic growth capacity of neurons and to facilitate axonal regeneration in the central nervous system after injury. The deletion of the mTOR negative regulator phosphatase and tensin homolog （PTEN） enhances regeneration of adult corticospinal neurons and ganglion cells. In the present study, we used a tyrosine-mutated （Y444F） AAV2 vector to efficiently express a short hairpin RNA （shRNA） for silencing PTEN expression in retinal ganglion cells. We evaluated cell survival and axonal regeneration in a rat model of optic nerve axotomy. The rats received an intravitreal injection of wildtype AAV2 or Y444F mutant AAV2 （both carrying shRNA to PTEN） 4 weeks before optic nerve axotomy. Compared with the wildtype AAV2 vector, the Y444F mutant AAV2 vector enhanced retinal ganglia cell survival and stimulated axonal regeneration to a greater extent 6 weeks after axotomy. Moreover,post-axotomy injection of the Y444F AAV2 vector expressing the shRNA to PTEN rescued ～19% of retinal ganglion cells and induced axons to regenerate near to the optic chiasm. Taken together, our results demonstrate that PTEN knockdown with the Y444F AAV2 vector promotes retinal ganglion cell survival and stimulates long-distance axonal regeneration after optic nerve axotomy. Therefore, the Y444F AAV2 vector might be a promising gene therapy tool for treating optic nerve injury.

Electric stimulation and decimeter wave therapy improve the recovery of injured sciatic nerves

Drug treatment, electric stimulation and decimeter wave therapy have been shown to promote the repair and regeneration of the peripheral nerves at the injured site. This study prepared a Mackinnon’s model of rat sciatic nerve compression. Electric stimulation was given immediately after neurolysis, and decimeter wave radiation was performed at 1 and 12 weeks post-operation. Histological observation revealed that intraoperative electric stimulation and decimeter wave therapy could improve the local blood circulation of repaired sites, alleviate hypoxia of compressed nerves, and lessen adhesion of compressed nerves, thereby decreasing the formation of new entrapments and enhancing compressed nerve regeneration through an improved microenvironment for regeneration. Immunohistochemical staining results revealed that intraoperative electric stimulation and decimeter wave could promote the expression of S-100 protein. Motor nerve conduction velocity and amplitude, the number and diameter of myelinated nerve fibers, and sciatic functional index were significantly increased in the treated rats. These results verified that intraoperative electric stimulation and decimeter wave therapy contributed to the regeneration and the recovery of the functions in the compressed nerves.

Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury

Ras homolog enriched in brain(Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1(mTORC1).Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR.S6K1 and4E-BP1 are important downstream effectors of mTORC1.In this study,we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1in the protection of retinal ganglion cells.We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration.We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute(14 days) and chronic(21 and 42 days) stages of injury.We also found that either co-expression of the dominant-negative S6K1mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells.This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration.However,only S6K1 activation,but not 4E-BP1 knockdown,induced axon regeneration when applied alone.Furthermore,S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury,whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days postinjury.Ove rexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury.Likewise,co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury.These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rhe b/mTOR.Together,our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity.Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.

不同运动方式促进周围神经损伤后的功能恢复

背景:运动作为一种主动康复的方式可以改善周围神经损伤导致的功能障碍,而不同运动方式针对的病变部位及恢复机制不同。目的:综合分析不同运动方式在周围神经损伤功能恢复中的应用及机制。方法:应用计算机检索中国知网、PubMed数据库建库时间至2024年1月期间的相关文献,英文检索词为“peripheral nerves injury,spinal cord,exercise,cerebral cortex,muscle atrophy,mirror therapy,blood flow restriction training”,中文检索词为“周围神经损伤,脊髓,大脑皮质,肌肉萎缩,有氧运动,血流限制,镜像运动”,最终纳入77篇文献进行分析。结果与结论:周围神经损伤后会引起其支配骨骼肌萎缩、相应脊髓节段病变、感觉运动皮质重塑等系统性的病理变化。有氧运动可以加强免疫反应,促进神经胶质细胞极化以及神经生长因子的释放,改善功能障碍。血流限制运动可以调节肌肉生长因子的分泌,促进肌肉生长及增强肌肉力量。镜像运动在激活大脑皮质、减少皮质重塑方面有良好的作用。不同运动方式在周围神经损伤功能恢复中具有潜在的益处,然而目前仍存在一些问题和挑战,例如运动方式的选择、运动强度和频率的控制及机制的详细解析等。

富血小板血浆及水凝胶治疗脊髓损伤

背景:大量文献报道了富血小板血浆、水凝胶治疗脊髓损伤的作用及其机制,但较少文章归纳总结它们治疗脊髓损伤的策略。目的:归纳总结脊髓损伤的病理进程,富血小板血浆和水凝胶单独及联合应用修复脊髓损伤的策略。方法:应用计算机检索Pub Med和中国知网数据库建库至2024年3月之前发表的文献,中文检索词为“脊髓损伤,富血小板血浆,水凝胶”,英文检索词为“spinal cord injury,spinal cord,Platelet-rich plasma,hydrogel,angiogenesis,neuralgia,combination therapy”,按照纳入和排除标准对文献进行筛选,最终纳入128篇文献进行综述分析。结果与结论:(1)富血小板血浆的分类复杂多样,在脊髓损伤的修复性治疗应用中的效果也是各有不同,但都表现出一定的积极的效果,即具有一定的促进轴突再生、刺激血管生成、治疗神经性疼痛等作用;(2)富血小板血浆的作用主要得益于其所含的生长因子等成分;(3)水凝胶的种类也很多,在脊髓损伤的修复性治疗中主要起到填充、模拟细胞外基质、搭载药物与生物产品、作为支架搭载细胞等作用;(4)与单一的治疗方式相比,富血小板血浆和水凝胶联合治疗可更有效地促进神经再生和脊髓功能的恢复。

Efficacy of epalrestat plus α-lipoic acid combination therapy versus monotherapy in patients with diabetic peripheral neuropathy: a meta-analysis of 20 randomized controlled trials

OBJECTIVE： To evaluate the efficacy of α-lipoic acid（ALA） plus epalrestat combination therapy in the treatment of diabetic peripheral neuropathy（DPN）. DATA SOURCES： The electronic databases of Pub Med, Medline, Embase, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Wanfang Database and the Chinese Biomedical Database were used to retrieve relevant studies without language restrictions. The search was conducted from the inception of each database to 7 October 2016. The key terms were（diabetic peripheral neuropathy or diabetic neuropathy or DPN） AND（α-lipoic acid or lipoic acid or thioctic acid） AND epalrestat. DATA SELECTION： All of the eligible studies met the following inclusion criteria：（1） Randomized controlled trials that compared efficacy and safety of epalrestat plus ALA combination therapy versus epalrestat or ALA monotherapy in patients with DPN.（2） The minimum duration of treatment was 2 weeks.（3） The DPN patients were diagnosed using the World Health Organization standardized type 2 diabetes mellitus and DPN criteria.（4） Studies contained at least one measure that could reflect the efficacy of the drug and nerve conduction velocities. Studies in which the control group used epalrestat or ALA combined with other drugs were excluded. Statistical analyses were performed using STATA software for meta-analysis. OUTCOME MEASURES： The primary outcomes were the therapeutic efficacy, median motor nerve conduction velocity（MNCV）, median sensory nerve conduction velocity（SNCV）, peroneal MNCV and peroneal SNCV.RESULTS： Twenty studies with 1894 DPN patients were included, including 864 patients in the ALA plus epalrestat group, 473 in the ALA group and 557 in the epalrestat group. The efficacy of ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies（RR = 1.29, 95% CI： 1.21–1.38; RR = 1.43, 95% CI： 1.34–1.54, respectively）. ALA plus epalrestat combination therapy also significantly improved median MNCV（WMD = 5.41, 95% CI： 2.07–8.75）, median SNCV（WMD = 5.87, 95% CI： 1.52–10.22）, peroneal MNCV（WMD = 5.59, 95% CI： 2.70–8.47） and peroneal SNCV（WMD = 4.57, 95% CI： 2.46–6.68）.CONCLUSION： ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies for clinical efficacy and nerve conduction velocities in patients with DPN.

Constraint-induced movement therapy enhances angiogenesis and neurogenesis after cerebral ischemia/reperfusion

Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke.In addition,it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling.Here,a stroke model was established by middle cerebral artery occlusion and reperfusion.Seven days after stroke,the following treatments were initiated and continued for 3 weeks:forced limb use in constraint-induced movement therapy rats(constraint-induced movement therapy group),intraperitoneal infusion of fasudil(a ROCK inhibitor)in fasudil rats(fasudil group),or lateral ventricular injection of NEP1-40(a specific antagonist of the Nogo-66 receptor)in NEP1-40 rats(NEP1-40 group).Immunohistochemistry and western blot assay results showed that,at 2 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone.However,at 4 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups,but there was no difference between these two groups.Compared with the ischemia/reperfusion group,modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion,especially in the constraint-induced movement therapy group.Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers(BrdU in combination with CD31(platelet endothelial cell adhesion molecule),Nestin,doublecortin,NeuN,and glial fibrillary acidic protein)in the subventricular zone and ischemic boundary zone ipsilateral to the infarct.After 3 weeks of constraint-induced movement therapy,the number of regenerated nerve cells was noticeably increased,and was accompanied by an increased immune response of tight junctions(claudin-5),a pericyte marker(a-smooth muscle actin),and vascular endothelial growth factor receptor 2.Taken together,the results demonstrate that,compared with fasudil,constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion.In addition,constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40.Therefore,constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury,at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway.All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University,China on December 9,2015(approval No.2015 PS326 K).

Early constraint-induced movement therapy affects behavior and neuronal plasticity in ischemia-injured rat brains

Constraint-induced movement therapy is an effective rehabilitative training technique used to improve the restoration of impaired upper extremity movement after stroke. However, whether constraint-induced movement therapy is more effective than conventional rehabilitation in acute or sub-acute stroke remains controversial. The aim of the present study was to identify the optimal time to start constraint-induced movement therapy after ischemic stroke and to explore the mechanisms by which constraint-induced movement therapy leads to post-stroke recovery. Sixty-four adult male Sprague-Dawley rats were randomly divided into four groups: sham-surgery group, cerebral ischemia/reperfusion group, early constraint-induced movement therapy group, and late constraint-induced movement therapy group. Rat models of left middle cerebral artery occlusion were established according to the Zea Longa line embolism method. Constraint-induced movement therapy was conducted starting on day 1 or day 14 in the early constraint-induced movement therapy and late constraint-induced movement therapy groups, respectively. To explore the effect of each intervention time on neuromotor function, behavioral function was assessed using a balance beam walking test before surgery and at 8 and 21 days after surgery. The expression levels of brain-derived neurotrophic factor, nerve growth factor and Nogo receptor were evaluated using real time-polymerase chain reaction and western blot assay to assess the effect of each intervention time. The results showed that the behavioral score was significantly lower in the early constraint-induced movement therapy group than in the cerebral ischemia/reperfusion and late constraint-induced movement therapy groups at 8 days. At 21 days, the scores had significantly decreased in the early constraint-induced movement therapy and late constraint-induced movement therapy groups. At 8 days, only mild pyknosis appeared in neurons of the ischemic penumbra in the early constraint-induced movement therapy group, which was distinctly better than in the cerebral ischemia/reperfusion group. At 21 days, only a few vacuolated cells were observed and no obvious inflammatory cells were visible in late constraint-induced movement therapy group, which was much better than at 8 days. The mRNA and protein expression levels of brain-derived neurotrophic factor and nerve growth factor were significantly higher, but expression levels of Nogo receptor were significantly lower in the early constraint-induced movement therapy group compared with the cerebral ischemia/reperfusion and late constraint-induced movement therapy groups at 8 days. The changes in expression levels at 21 days were larger but similar in both the early constraint-induced movement therapy and late constraint-induced movement therapy groups. Besides, the protein nerve growth factor level was higher in the late constraint-induced movement therapy group than in the early constraint-induced movement therapy group at 21 days. These results suggest that both early(1 day) and late(14 days) constraint-induced movement therapy induces molecular plasticity and facilitates functional recovery after ischemic stroke, as illustrated by the histology. The mechanism may be associated with downregulation of Nogo receptor expression and upregulation of brain-derived neurotrophic factor and nerve growth factor expression.

Constraint-induced movement therapy in treatment of acute and sub-acute stroke: a meta-analysis of 16 randomized controlled trials

OBJECTIVE： The aim of this meta-analysis was to evaluate the clinical efficacy of constraint-induced movement therapy in acute and sub-acute stroke. DATA SOURCES： The key words were stroke, cerebrovascular accident, constraint-induced therapy, forced use, and randomized controlled trial. The databases, including China National Knowledge Infrastructure, WanFang, Weipu Information Resources System, Chinese Biomedical Literature Database, PubMed, Med- line, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, were searched for studies on randomized controlled trials for treating acute or sub-acute stroke published before March 2016. DATA SELECTION： We retrieved relevant randomized controlled trials that compared constraint-induced movement therapy in treatment of acute or sub-acute stroke with traditional rehabilitation therapy （tradi- tional occupational therapy）. Patients were older than 18 years, had disease courses less than 6 months, and were evaluated with at least one upper extremity function scale. Study quality was evaluated, and data that met the criteria were extracted. Stata 11.0 software was used for the meta-analysis. OUTCOME MEASURES： Fugl-Meyer motor assessment of the arm, the action research-arm test, a motor activity log for amount of use and quality of movement, the Wolf motor function test, and a modified Bar- thel index. RESULTS： A total of 16 prospective randomized controlled trials （379 patients in the constraint-induced movement-therapy group and 359 in the control group） met inclusion criteria. Analysis showed significant mean differences in favor of constraint-induced movement therapy for the Fugl-Meyer motor assessment of the arm （weighted mean difference （WMD） = 10.822; 95% confidence intervals （95% CI）： 7.419-14.226）, the action research-arm test （WMD = 10.718; 95% CI： 5.704-15.733）, the motor activity log for amount of use and quality of movement （WMD = 0.812; 95% CI： 0.331-1.293） and the modified Barthel index （WMD = 10.706; 95% CI： 4.417-16.966）. CONCLUSION： Constraint-induced movement therapy may be more beneficial than traditional rehabili- tation therapy for improving upper limb function after acute or sub-acute stroke.

Speech and language therapy for aphasia following subacute stroke

The aim of this study was to investigate the time window, duration and intensity of optimal speech and language therapy applied to aphasic patients with subacute stroke in our hospital. The study consisted of 33 patients being hospitalized for stroke rehabilitation in our hospital with first stroke but without previous history of speech and language therapy. Sixteen sessions of impairment-based speech and language therapy were applied to the patients, 30-60 minutes per day, 2 days a week, for 8 successive weeks. Aphasia assess- ment in stroke patients was performed with Giilhane Aphasia Test-2 before and after treatment. Compared with before treatment, fluency of speech, listening comprehension, reading comprehension, oral motor evaluation, automatic speech, repetition and naming were improved after treatment. This suggests that 16 seesions of speech and language therapy, 30-60 minutes per day, 2 days a week, for 8 successive weeks, are effective in the treatment of aphasic patients with subacute stroke.

The role of undifferentiated adipose-derived stem cells in peripheral nerve repair

Peripheral nerve injuries impose significant health and economic consequences, yet no surgical repair can deliver a complete recovery of sensory or motor function. Traditional methods of repair are less than ideal： direct coaptation can only be performed when tension-free repair is possible, and transplantation of nerve autograft can cause donor-site morbidity and neuroma formation. Cell-based therapy delivered via nerve conduits has thus been explored as an alternative method of nerve repair in recent years. Stem cells are promising sources of the regenerative core material in a nerve conduit because stem cells are multipotent in function, abundant in supply, and more accessible than the myelinating Schwann cells. Among different types of stem cells, undifferentiated adipose-derived stem cell（uASC）, which can be processed from adipose tissue in less than two hours, is a promising yet underexplored cell type. Studies of uASC have emerged in the past decade and have shown that autologous uASCs are non-immunogenic, easy to access, abundant in supply, and efficacious at promoting nerve regeneration. Two theories have been proposed as the primary regenerative mechanisms of uASC： in situ trans-differentiation towards Schwann cells, and secretion of trophic and anti-inflammatory factors. Future studies need to fully elucidate the mechanisms, side effects, and efficacy of uASC-based nerve regeneration so that uASCs can be utilized in clinical settings.

Current status and future prospects of stem cell therapy in Alzheimer’s disease

Alzheimer’s disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer’s disease, and the current state of stem cell transplantation in the treatment of Alzheimer’s disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer’s disease.

Aerobic exercise combined with huwentoxin-I mitigates chronic cerebral ischemia injury

Ca2＋ channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I （HWTX-I）, a spider peptide toxin that blocks Ca2＋ channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I ＋ aerobic exercise group. The combined effects of HWTX I and exercise were superior to HWTX-I or aerobic exercise alone. HWTX-I effectively activated the Notch signal transduction pathway in brain tissue. Aerobic exercise up-regulated synaptophysin mRNA expression. These results demonstrated that aerobic exercise, in combination with HWTX-I, effectively relieved neuronal injury induced by chronic cerebral ischemia via the Notch signaling pathway and promoting synaptic regeneration.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Temporal changes in the spinal cord transcriptome after peripheral nerve injury

Peripheral nerve injury may trigger changes in mRNA levels in the spinal cord.Finding key mRNAs is important for improving repair after nerve injury.This study aimed to investigate changes in mRNAs in the spinal cord following sciatic nerve injury by transcriptomic analysis.The left sciatic nerve denervation model was established in C57 BL/6 mice.The left L4–6 spinal cord segment was obtained at 0,1,2,4 and 8 weeks after severing the sciatic nerve.mRNA expression profiles were generated by RNA sequencing.The sequencing results of spinal cord mRNA at 1,2,4,and 8 weeks after severing the sciatic nerve were compared with those at 0 weeks by bioinformatic analysis.We identified 1915 differentially expressed mRNAs in the spinal cord,of which 4,1909,and 2 were differentially expressed at 1,4,and 8 weeks after sciatic nerve injury,respectively.Sequencing results indicated that the number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury.These mRNAs were associated with the cellular response to lipid,ATP metabolism,energy coupled proton transmembrane transport,nuclear transcription factor complex,vacuolar proton-transporting V-type ATPase complex,inner mitochondrial membrane protein complex,tau protein binding,NADH dehydrogenase activity and hydrogen ion transmembrane transporter activity.Of these mRNAs,Sgk1,Neurturin and Gpnmb took part in cell growth and development.Pathway analysis showed that these mRNAs were mainly involved in aldosterone-regulated sodium reabsorption,oxidative phosphorylation and collecting duct acid secretion.Functional assessment indicated that these mRNAs were associated with inflammation and cell morphology development.Our findings show that the number and type of spinal cord mRNAs involved in changes at different time points after peripheral nerve injury were different.The number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury.These results provide reference data for finding new targets for the treatment of peripheral nerve injury,and for further gene therapy studies of peripheral nerve injury and repair.The study procedures were approved by the Ethics Committee of the Peking University People's Hospital(approval No.2017 PHC004)on March 5,2017.