Rat models of acute spinal cord injury and sciatic nerve injury were established. Apelin expression in spinal cord tissue was determined. In normal rat spinal cords, apelin expression was visible; however, 2 hours pos...Rat models of acute spinal cord injury and sciatic nerve injury were established. Apelin expression in spinal cord tissue was determined. In normal rat spinal cords, apelin expression was visible; however, 2 hours post spinal cord injury, apelin expression peaked. Apelin expression increased 1 day post ligation of the sciatic nerve compared with normal rat spinal cords, and peaked at 3 days. Apelin expression was greater in the posterior horn compared with the anterior horn at each time point when compared with the normal group. The onset of neuronal apoptosis was significantly delayed following injection of apelin protein at the stump of the sciatic nerve, and the number of apoptotic cells after injury was reduced when compared with normal spinal cords. Our results indicate that apelin is expressed in the normal spinal cord and central nervous system after peripheral nerve injury. Apelin protein can reduce motor neuron apoptosis in the spinal cord anterior horn and delay the onset of apoptosis.展开更多
The visual pathway have 6 parts, involving optic nerve, optic chiasm, optic tract, lateral geniculate body, optic radiation and cortical striatum area. Corresponding changes may be found in these 6 parts following opt...The visual pathway have 6 parts, involving optic nerve, optic chiasm, optic tract, lateral geniculate body, optic radiation and cortical striatum area. Corresponding changes may be found in these 6 parts following optic nerve injury. At present, studies mainly focus on optic nerve and retina, but studies on lateral geniculate body are few. OBJECTIVE: To prepare models of acute optic nerve injury for observing the changes of neurons in lateral geniculate body, expression of neurofilament protein at different time after injury and cell apoptosis under the optical microscope, and for investigating the changes of neurons in lateral geniculate body following acute optic nerve injury. DESIGN: Completely randomized grouping design, controlled animal experiment. SETTING: Department of Neurosurgery, General Hospital of Ji'nan Military Area Command of Chinese PLA. MATERIALS: Twenty-eight adult healthy cats of either gender and common grade, weighing from 2.0 to 3.5 kg, were provided by the Animal Experimental Center of Fudan University. The involved cats were divided into 2 groups according to table of random digit: normal control group (n=3) and model group (n=25). Injury 6 hours, l, 3, 7 and 14 days five time points were set in model group for later observation, 5 cats at each time point. TUNEL kit (Bohringer-Mannheim company )and NF200& Mr 68 000 mouse monoclonal antibody (NeoMarkers Company) were used in this experiment. METHODS: This experiment was carded out in the Department of Neurosurgery, General Hospital of Ji'nan Military Area Command of Chinese PLA between June 2004 and June 2005.① The cats of model group were developed into cat models of acute intracranial optic nerve injury as follows: The anesthetized cats were placed in lateral position. By imitating operation to human, pterion approach was used. An incision was made at the joint line between outer canthus and tragus, and deepened along cranial base until white optic nerve via optic nerve pore and further to brain tissue. Optic nerve about 3 mm was liberated and occluded by noninvasive vascular clamp for 20 s. After removal of noninvasive vascular clamp, the area compressed by optic nerve was hollowed and narrowed, but non-fractured. Skull was closed when haemorrhage was not found. Bilateral pupillary size, direct and indirect light reflect were observed. Operative side pupil was enlarged as compared with opposite side, direct light reflect disappeared and indirect light reflect existed, which indicated that the models were successful. Animals of control group were not modeled .② The animals in the control group and model group were sacrificed before and 6 hours, 1, 3, 7 and 14 days after modeling respectively. Lateral geniculate body sample was taken and performed haematoxylin & eosin staining. Immunohistochemical staining showed lateral geniculate body neurofilament protein expression, and a comparison of immunohistochemial staining results was made between experimental group and control group. Terminal deoxynucleo-tidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) was used to label apoptotic cells in lateral geniculate body. MAIN OUTCOME MEASURES: Neuronal morphological change, neurofilament protein expression and cell apoptosis in lateral geniculate body following acute optic nerve injury. RESULTS: Twenty-eight involved cats entered the final analysis. ① Histological observation results: In the control group, cell processes were obviously found, which were few or shortening in the model group. ② Neuronal neurofilament protein expression: Cells in lateral geniculate body in the control group and at 6 hours after injury presented clear strip-shaped staining, and those at 7 and 14 days presented irregular distribution without layers and obviously decreasing staining intensity. The positive rate of neurofilament protein in lateral geniculate body in control group and 6 hours, l, 3, 7 and 14 days after injury was ( 10.22±0.42) %, (10.03±0.24) %, (9.94±0.14) %, (9.98±0.22) %, (8.18±0.34) % and (6.37±0.18)%, respectively. Positive rate of neurofilament protein in control group, at 6 hours, 1 or 3 days after injury was significantly different from that at 7 days after injury (P 〈 0.05); Positive rate of neurofilament protein in control group, at 6 hours, 1, 3 or 7 days after injury was significantly different from that at 14 days after injury (P 〈 0.05). It indicated that neuronal injury in lateral geniculate body was not obvious within short term after optic nerve injury, but obvious at 7 days after injury and progressively aggravated until at 14 days after injury.③ Neuronal apoptosis: TUNEL staining showed that neuronal apoptosis in lateral geniculate body appeared at 7 days after injury, and a Lot of neuronal apoptosis in lateral geniculate body was found at 14 days after injury. It indicated that neuronal injury in lateral geniculate body was related to apoptosis. CONCLUSION: In short term after optic nerve injury (within 7 days), nerve injury of lateral geniculate body is not obvious, then, it will aggravate with the elongation of injury time. The occurrence of neuronal iniury of lateral geniculate body is related to the apoptosis of nerve cells.展开更多
The peripheral nervous system has an extensive branching organization, and peripheral nerve injuries that ablate branch points present a complex challenge for clinical repair. Ablations of linear segments of the PNS h...The peripheral nervous system has an extensive branching organization, and peripheral nerve injuries that ablate branch points present a complex challenge for clinical repair. Ablations of linear segments of the PNS have been extensively studied and routinely treated with autografts, acellular nerve allografts, conduits, wraps, and nerve transfers. In contrast, segmental-loss peripheral nerve injuries, in which one or more branch points are ablated so that there are three or more nerve endings, present additional complications that have not been rigorously studied or documented. This review discusses:(1) the branched anatomy of the peripheral nervous system,(2) case reports describing how peripheral nerve injuries with branched ablations have been surgically managed,(3) factors known to influence regeneration through branched nerve structures,(4) techniques and models of branched peripheral nerve injuries in animal models, and(5) conclusions regarding outcome measures and studies needed to improve understanding of regeneration through ablated branched structures of the peripheral nervous system.展开更多
The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neuro...The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.展开更多
Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to...Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.展开更多
Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide ...Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.展开更多
Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various disea...Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifical...Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifically up-regulated in Schwann cells.Furthermore,using Schwann cell-specific Runx2 knocko ut mice,we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent.Changes observed in Runx2 knoc kout mice include increased prolife ration of Schwann cells,impaired Schwann cell migration and axonal regrowth,reduced re-myelination of axo ns,and a block in macrophage clearance in the late stage of regeneration.Taken together,our findings indicate that Runx2 is a key regulator of Schwann cell plasticity,and therefore peripheral nerve repair.Thus,our study shows that Runx2 plays a major role in Schwann cell migration,re-myelination,and peripheral nerve functional recovery following injury.展开更多
Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene g...Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves.We have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor recovery.Furthermore,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target muscles.In this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve.Young adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of PEG.Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site.The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively.At 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase.PEG-fusion repair reestablished axonal continuity.Compared to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal areas.Unexpectedly,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair.This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair,supporting the use of this novel repair methodology over currently available treatments.展开更多
Unlike central nervous system injuries,peripheral nerve injuries(PNIs)are often characterized by more or less successful axonal regeneration.However,structural and functional recovery is a senile process involving mul...Unlike central nervous system injuries,peripheral nerve injuries(PNIs)are often characterized by more or less successful axonal regeneration.However,structural and functional recovery is a senile process involving multifaceted cellular and molecular processes.The contemporary treatment options are limited,with surgical intervention as the gold-standard method;however,each treatment option has its associated limitations,especially when the injury is severe with a large gap.Recent advancements in cell-based therapy and cell-free therapy approaches using stem cell-derived soluble and insoluble components of the cell secretome are fast-emerging therapeutic approaches to treating acute and chronic PNI.The recent pilot study is a leap forward in the field,which is expected to pave the way for more enormous,systematic,and well-designed clinical trials to assess the therapeutic efficacy of mesenchymal stem cell-derived exosomes as a bio-drug either alone or as part of a combinatorial approach,in an attempt synergize the best of novel treatment approaches to address the complexity of the neural repair and regeneration.展开更多
Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies a...Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.展开更多
Autografting is the gold standard for surgical repair of nerve defects>5 mm in length;however,autografting is associated with potential complications at the nerve donor site.As an alternative,nerve guidance conduit...Autografting is the gold standard for surgical repair of nerve defects>5 mm in length;however,autografting is associated with potential complications at the nerve donor site.As an alternative,nerve guidance conduits may be used.The ideal conduit should be flexible,resistant to kinks and lumen collapse,and provide physical cues to guide nerve regeneration.We designed a novel flexible conduit using electrospinning technology to create fibers on the innermost surface of the nerve guidance conduit and employed melt spinning to align them.Subsequently,we prepared disordered electrospun fibers outside the aligned fibers and helical melt-spun fibers on the outer wall of the electrospun fiber lumen.The presence of aligned fibers on the inner surface can promote the extension of nerve cells along the fibers.The helical melt-spun fibers on the outer surface can enhance resistance to kinking and compression and provide stability.Our novel conduit promoted nerve regeneration and functional recovery in a rat sciatic nerve defect model,suggesting that it has potential for clinical use in human nerve injuries.展开更多
Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that ...Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.展开更多
FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways ...FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.展开更多
Peripheral nerves are essential components of the human body’s communication system,transmitting signals between the central nervous system and various body parts.Damage resulting from trauma or disease can result in...Peripheral nerves are essential components of the human body’s communication system,transmitting signals between the central nervous system and various body parts.Damage resulting from trauma or disease can result in debilitating sensory and motor deficits.Nerve injuries,particularly those resulting in significant gaps in the nerve tissue,pose a formidable challenge for clinicians and researchers.Despite their limitations,including limited availability and donor site morbidity,nerve autografts remain the clinical gold standard for treating nerve injuries.展开更多
Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network lev...Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network level have not been elucidated.This study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve transfer.Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper trunk.Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery.The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component.Alterations in intra-network resting-state functional connectivity were compared among the groups.Target muscle reinnervation was assessed by behavioral observation(elbow flexion)and electromyography.The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway.Nerve repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation.The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer.Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer.Our study revealed important brain networks related to different nerve reconstructions.These networks may be potential targets for enhancing motor recovery.展开更多
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulat...Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.展开更多
Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve rep...Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.展开更多
Peripheral nerve injury(PNI)is a common neurological disorder and complete functional recovery is difficult to achieve.In recent years,bone marrow mesenchymal stem cells(BMSCs)have emerged as ideal seed cells for PNI ...Peripheral nerve injury(PNI)is a common neurological disorder and complete functional recovery is difficult to achieve.In recent years,bone marrow mesenchymal stem cells(BMSCs)have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous trans-plantation ability.This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI.The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury.BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors,extracellular matrix molecules,and adhesion molecules.Additionally,BMSCs release pro-angiogenic factors to promote the formation of new blood vessels.They modulate cytokine expression and regulate macrophage polarization,leading to immunomodulation.Furthermore,BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration,thereby promoting neuronal repair and regeneration.Moreover,this review explores methods of applying BMSCs in PNI treatment,including direct cell trans-plantation into the injured neural tissue,implantation of BMSCs into nerve conduits providing support,and the application of genetically modified BMSCs,among others.These findings confirm the potential of BMSCs in treating PNI.However,with the development of this field,it is crucial to address issues related to BMSC therapy,including establishing standards for extracting,identifying,and cultivating BMSCs,as well as selecting application methods for BMSCs in PNI such as direct transplantation,tissue engineering,and genetic engineering.Addressing these issues will help translate current preclinical research results into clinical practice,providing new and effective treatment strategies for patients with PNI.展开更多
文摘Rat models of acute spinal cord injury and sciatic nerve injury were established. Apelin expression in spinal cord tissue was determined. In normal rat spinal cords, apelin expression was visible; however, 2 hours post spinal cord injury, apelin expression peaked. Apelin expression increased 1 day post ligation of the sciatic nerve compared with normal rat spinal cords, and peaked at 3 days. Apelin expression was greater in the posterior horn compared with the anterior horn at each time point when compared with the normal group. The onset of neuronal apoptosis was significantly delayed following injection of apelin protein at the stump of the sciatic nerve, and the number of apoptotic cells after injury was reduced when compared with normal spinal cords. Our results indicate that apelin is expressed in the normal spinal cord and central nervous system after peripheral nerve injury. Apelin protein can reduce motor neuron apoptosis in the spinal cord anterior horn and delay the onset of apoptosis.
文摘The visual pathway have 6 parts, involving optic nerve, optic chiasm, optic tract, lateral geniculate body, optic radiation and cortical striatum area. Corresponding changes may be found in these 6 parts following optic nerve injury. At present, studies mainly focus on optic nerve and retina, but studies on lateral geniculate body are few. OBJECTIVE: To prepare models of acute optic nerve injury for observing the changes of neurons in lateral geniculate body, expression of neurofilament protein at different time after injury and cell apoptosis under the optical microscope, and for investigating the changes of neurons in lateral geniculate body following acute optic nerve injury. DESIGN: Completely randomized grouping design, controlled animal experiment. SETTING: Department of Neurosurgery, General Hospital of Ji'nan Military Area Command of Chinese PLA. MATERIALS: Twenty-eight adult healthy cats of either gender and common grade, weighing from 2.0 to 3.5 kg, were provided by the Animal Experimental Center of Fudan University. The involved cats were divided into 2 groups according to table of random digit: normal control group (n=3) and model group (n=25). Injury 6 hours, l, 3, 7 and 14 days five time points were set in model group for later observation, 5 cats at each time point. TUNEL kit (Bohringer-Mannheim company )and NF200& Mr 68 000 mouse monoclonal antibody (NeoMarkers Company) were used in this experiment. METHODS: This experiment was carded out in the Department of Neurosurgery, General Hospital of Ji'nan Military Area Command of Chinese PLA between June 2004 and June 2005.① The cats of model group were developed into cat models of acute intracranial optic nerve injury as follows: The anesthetized cats were placed in lateral position. By imitating operation to human, pterion approach was used. An incision was made at the joint line between outer canthus and tragus, and deepened along cranial base until white optic nerve via optic nerve pore and further to brain tissue. Optic nerve about 3 mm was liberated and occluded by noninvasive vascular clamp for 20 s. After removal of noninvasive vascular clamp, the area compressed by optic nerve was hollowed and narrowed, but non-fractured. Skull was closed when haemorrhage was not found. Bilateral pupillary size, direct and indirect light reflect were observed. Operative side pupil was enlarged as compared with opposite side, direct light reflect disappeared and indirect light reflect existed, which indicated that the models were successful. Animals of control group were not modeled .② The animals in the control group and model group were sacrificed before and 6 hours, 1, 3, 7 and 14 days after modeling respectively. Lateral geniculate body sample was taken and performed haematoxylin & eosin staining. Immunohistochemical staining showed lateral geniculate body neurofilament protein expression, and a comparison of immunohistochemial staining results was made between experimental group and control group. Terminal deoxynucleo-tidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) was used to label apoptotic cells in lateral geniculate body. MAIN OUTCOME MEASURES: Neuronal morphological change, neurofilament protein expression and cell apoptosis in lateral geniculate body following acute optic nerve injury. RESULTS: Twenty-eight involved cats entered the final analysis. ① Histological observation results: In the control group, cell processes were obviously found, which were few or shortening in the model group. ② Neuronal neurofilament protein expression: Cells in lateral geniculate body in the control group and at 6 hours after injury presented clear strip-shaped staining, and those at 7 and 14 days presented irregular distribution without layers and obviously decreasing staining intensity. The positive rate of neurofilament protein in lateral geniculate body in control group and 6 hours, l, 3, 7 and 14 days after injury was ( 10.22±0.42) %, (10.03±0.24) %, (9.94±0.14) %, (9.98±0.22) %, (8.18±0.34) % and (6.37±0.18)%, respectively. Positive rate of neurofilament protein in control group, at 6 hours, 1 or 3 days after injury was significantly different from that at 7 days after injury (P 〈 0.05); Positive rate of neurofilament protein in control group, at 6 hours, 1, 3 or 7 days after injury was significantly different from that at 14 days after injury (P 〈 0.05). It indicated that neuronal injury in lateral geniculate body was not obvious within short term after optic nerve injury, but obvious at 7 days after injury and progressively aggravated until at 14 days after injury.③ Neuronal apoptosis: TUNEL staining showed that neuronal apoptosis in lateral geniculate body appeared at 7 days after injury, and a Lot of neuronal apoptosis in lateral geniculate body was found at 14 days after injury. It indicated that neuronal injury in lateral geniculate body was related to apoptosis. CONCLUSION: In short term after optic nerve injury (within 7 days), nerve injury of lateral geniculate body is not obvious, then, it will aggravate with the elongation of injury time. The occurrence of neuronal iniury of lateral geniculate body is related to the apoptosis of nerve cells.
基金University of Wyoming Startup funds,United States Department of Defense,No. W81XWH-17-1-0402 (to JSB)the University of Wyoming Sensory Biology COBRE under National Institutes of Health (NIH),No. 5P20GM121310-02 (to JSB)+2 种基金the National Institute of General Medical Sciences of the NIH,No. P20GM103432 (to JSB)DOD AFIRM III,No. W81XWH-20-2-0029 (to GDB)a Lone Star Paralysis Foundation gi?t (to GDB)。
文摘The peripheral nervous system has an extensive branching organization, and peripheral nerve injuries that ablate branch points present a complex challenge for clinical repair. Ablations of linear segments of the PNS have been extensively studied and routinely treated with autografts, acellular nerve allografts, conduits, wraps, and nerve transfers. In contrast, segmental-loss peripheral nerve injuries, in which one or more branch points are ablated so that there are three or more nerve endings, present additional complications that have not been rigorously studied or documented. This review discusses:(1) the branched anatomy of the peripheral nervous system,(2) case reports describing how peripheral nerve injuries with branched ablations have been surgically managed,(3) factors known to influence regeneration through branched nerve structures,(4) techniques and models of branched peripheral nerve injuries in animal models, and(5) conclusions regarding outcome measures and studies needed to improve understanding of regeneration through ablated branched structures of the peripheral nervous system.
基金supported by the National Natural Science Foundation of China,Nos.30772368(to DH),81371034(to XH)the Key Project of Natural Science Foundation of Shaanxi Province,No.2017JZ025(to DH).
文摘The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.
基金supported by the National Natural Science Foundation of China,Nos.31971277 and 31950410551(both to DY)。
文摘Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.
基金supported by the National Natural Science Foundation of China,No.32371048(to YK)the Peking University People’s Hospital Research and Development Funds,No.RDX2021-01(to YK)the Natural Science Foundation of Beijing,No.7222198(to NH)。
文摘Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.
基金supported by National Natural Science Foundation of China,No.32102745(to XL).
文摘Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
基金supported by the National Natural Science Foundation of China,No.82104795 (to RH)。
文摘Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifically up-regulated in Schwann cells.Furthermore,using Schwann cell-specific Runx2 knocko ut mice,we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent.Changes observed in Runx2 knoc kout mice include increased prolife ration of Schwann cells,impaired Schwann cell migration and axonal regrowth,reduced re-myelination of axo ns,and a block in macrophage clearance in the late stage of regeneration.Taken together,our findings indicate that Runx2 is a key regulator of Schwann cell plasticity,and therefore peripheral nerve repair.Thus,our study shows that Runx2 plays a major role in Schwann cell migration,re-myelination,and peripheral nerve functional recovery following injury.
基金supported by the Department of Defense AFIRMⅢW81XWH-20-2-0029 grant subcontractLone Star Paralysis gift,UT POC19-1774-13 grant+1 种基金Neuraptive Therapeutics Inc.26-7724-56 grantNational Institutes of Health R01-NS128086(all to GDB)。
文摘Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves.We have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor recovery.Furthermore,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target muscles.In this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve.Young adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of PEG.Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site.The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively.At 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase.PEG-fusion repair reestablished axonal continuity.Compared to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal areas.Unexpectedly,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair.This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair,supporting the use of this novel repair methodology over currently available treatments.
文摘Unlike central nervous system injuries,peripheral nerve injuries(PNIs)are often characterized by more or less successful axonal regeneration.However,structural and functional recovery is a senile process involving multifaceted cellular and molecular processes.The contemporary treatment options are limited,with surgical intervention as the gold-standard method;however,each treatment option has its associated limitations,especially when the injury is severe with a large gap.Recent advancements in cell-based therapy and cell-free therapy approaches using stem cell-derived soluble and insoluble components of the cell secretome are fast-emerging therapeutic approaches to treating acute and chronic PNI.The recent pilot study is a leap forward in the field,which is expected to pave the way for more enormous,systematic,and well-designed clinical trials to assess the therapeutic efficacy of mesenchymal stem cell-derived exosomes as a bio-drug either alone or as part of a combinatorial approach,in an attempt synergize the best of novel treatment approaches to address the complexity of the neural repair and regeneration.
基金supported by the German Research Foundation(DA 2255/1-1to SCD)+4 种基金a SickKids Research Training Competition(RESTRACOMP)Graduate Scholarship(to KJWS)an Ontario Graduate Scholarship(to KJWS)a grant from Natural Sciences and Engineering Research Council of Canada(NSERC)(to KJWS)a Kickstarter grant from the Institute of Biomedical Engineering(BME)at the University of Toronto(to KJWS)the Abe Frank Fund from the Riley’s Children Foundation(GHB)。
文摘Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
基金supported by the National Natural Science Foundation of China,No.82202718the Natural Science Foundation of Beijing,No.L212050the China Postdoctoral Science Foundation,Nos.2019M664007,2021T140793(all to ZL)。
文摘Autografting is the gold standard for surgical repair of nerve defects>5 mm in length;however,autografting is associated with potential complications at the nerve donor site.As an alternative,nerve guidance conduits may be used.The ideal conduit should be flexible,resistant to kinks and lumen collapse,and provide physical cues to guide nerve regeneration.We designed a novel flexible conduit using electrospinning technology to create fibers on the innermost surface of the nerve guidance conduit and employed melt spinning to align them.Subsequently,we prepared disordered electrospun fibers outside the aligned fibers and helical melt-spun fibers on the outer wall of the electrospun fiber lumen.The presence of aligned fibers on the inner surface can promote the extension of nerve cells along the fibers.The helical melt-spun fibers on the outer surface can enhance resistance to kinking and compression and provide stability.Our novel conduit promoted nerve regeneration and functional recovery in a rat sciatic nerve defect model,suggesting that it has potential for clinical use in human nerve injuries.
基金financially supported by the National Natural Science Foundation of China,Nos.82172104(to CX),81873767(to HZ)a grant from Jiangsu Provincial Research Hospital,Nos.YJXYY202204(to HZ),YJXYY202204-ZD04(to HZ)+5 种基金a grant from Jiangsu Provincial Key Medical CenterJiangsu Provincial Medical Innovation Center,No.CXZX202212Jiangsu Provincial Medical Key Discipline,No.ZDXK202240the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Technology Project of Nantong,No.MS22022008(to HZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX21_1457(to WW)。
文摘Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
基金supported by the National Natural Science Foundation of China,No.81971177(to YK)the Natural Science Foundation of Beijing,No.7222198(to NH)the Peking University People's Hospital Research and Development Fund,No.RDX2021-01(to YK)。
文摘FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.
基金supported by the Royal Thai Government Scholarship(to PM).
文摘Peripheral nerves are essential components of the human body’s communication system,transmitting signals between the central nervous system and various body parts.Damage resulting from trauma or disease can result in debilitating sensory and motor deficits.Nerve injuries,particularly those resulting in significant gaps in the nerve tissue,pose a formidable challenge for clinicians and researchers.Despite their limitations,including limited availability and donor site morbidity,nerve autografts remain the clinical gold standard for treating nerve injuries.
基金supported by the National Natural Science Foundation of China,Nos.81871836(to MZ),82172554(to XH),and 81802249(to XH),81902301(to JW)the National Key R&D Program of China,Nos.2018YFC2001600(to JX)and 2018YFC2001604(to JX)+3 种基金Shanghai Rising Star Program,No.19QA1409000(to MZ)Shanghai Municipal Commission of Health and Family Planning,No.2018YQ02(to MZ)Shanghai Youth Top Talent Development PlanShanghai“Rising Stars of Medical Talent”Youth Development Program,No.RY411.19.01.10(to XH)。
文摘Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network level have not been elucidated.This study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve transfer.Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper trunk.Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery.The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component.Alterations in intra-network resting-state functional connectivity were compared among the groups.Target muscle reinnervation was assessed by behavioral observation(elbow flexion)and electromyography.The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway.Nerve repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation.The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer.Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer.Our study revealed important brain networks related to different nerve reconstructions.These networks may be potential targets for enhancing motor recovery.
基金supported by the National Natural Science Foundation of China,Nos.82271411(to RG),51803072(to WLiu)grants from the Department of Finance of Jilin Province,Nos.2022SCZ25(to RG),2022SCZ10(to WLiu),2021SCZ07(to RG)+2 种基金Jilin Provincial Science and Technology Program,No.YDZJ202201ZYTS038(to WLiu)The Youth Support Programmed Project of China-Japan Union Hospital of Jilin University,No.2022qnpy11(to WLuo)The Project of China-Japan Union Hospital of Jilin University,No.XHQMX20233(to RG)。
文摘Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
基金supported by the National Natural Science Foundation of China,No.31870977(to HYS)the National Key Technologies Research and Development Program of China,No.2017YFA0104700(to FD)+2 种基金2022 Jiangsu Funding Program for Excellent Postdoctoral Talent(to MC)Priority Academic Program Development of Jiangsu Higher Education Institutions[PAPD]the Major Project of Basic Science(Natural Science)Research in Higher Education Institutions of Jiangsu Province,No.22KJA180001(to QRH)。
文摘Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.
基金CAMS Innovation Fund for Medical Sciences,No.2022-I2M-C&T-B-034.
文摘Peripheral nerve injury(PNI)is a common neurological disorder and complete functional recovery is difficult to achieve.In recent years,bone marrow mesenchymal stem cells(BMSCs)have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous trans-plantation ability.This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI.The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury.BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors,extracellular matrix molecules,and adhesion molecules.Additionally,BMSCs release pro-angiogenic factors to promote the formation of new blood vessels.They modulate cytokine expression and regulate macrophage polarization,leading to immunomodulation.Furthermore,BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration,thereby promoting neuronal repair and regeneration.Moreover,this review explores methods of applying BMSCs in PNI treatment,including direct cell trans-plantation into the injured neural tissue,implantation of BMSCs into nerve conduits providing support,and the application of genetically modified BMSCs,among others.These findings confirm the potential of BMSCs in treating PNI.However,with the development of this field,it is crucial to address issues related to BMSC therapy,including establishing standards for extracting,identifying,and cultivating BMSCs,as well as selecting application methods for BMSCs in PNI such as direct transplantation,tissue engineering,and genetic engineering.Addressing these issues will help translate current preclinical research results into clinical practice,providing new and effective treatment strategies for patients with PNI.