Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are...Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are incomplete and spare supraspinal pathways,especially those located within the peripheral white matter of the spinal cord,which includes reticulospinal pathways originating from the medullary reticular formation.Whereas there is abundant literature about the motor cortex,its corticospinal pathway,and its capacity to modulate functional recovery after SCI,less is known about the medullary reticular formation and its reticulospinal pathway.展开更多
The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,...The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).展开更多
Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and geneti...Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).展开更多
Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathop...Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.展开更多
Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people...Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).展开更多
Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues...Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.展开更多
Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regula...Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.展开更多
The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cel...The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cellular interactions and circuitry.Therapeutic interventions seek to modify some aspects of the injury course to enable the re-establishment of functional circuitry.Interventions often target one cell type(e.g.,promoting neuroprotection or neural regeneration)or one process(e.g.,modulating inflammation,affecting astrocytic,microglial,or macrophage responses.)Many axons in the spinal cord are myelinated,and after injury oligodendrocyte death causes demyelination.Promoting remyelination of spared or new axons to re-establish conduction seems a logical choice as a therapeutic target.展开更多
The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-...The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.展开更多
Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments...Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments,only a few studies have investigated the cellular and molecular consequences that occur in the brain after trauma.From the earliest stages,the injury triggers microglial activation,increased neuronal death,and reduced hippocampal neurogenesis in the dentate gyrus.展开更多
The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory ...The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory fibers.While the reticulospinal tract has been shown to be particularly prone to axonal growth and plasticity following injuries of the spinal cord,the differential capacities of excitatory and inhibitory fibers for plasticity remain unclear.As adaptive axonal plasticity involves a sophisticated interplay between excitatory and inhibitory input,we investigated in this study the plastic potential of glutamatergic(vGlut2)and GABAergic(vGat)fibers originating from the gigantocellular nucleus and the lateral paragigantocellular nucleus,two nuclei important for locomotor function.Using a combination of viral tracing,chemogenetic silencing,and AI-based kinematic analysis,we investigated plasticity and its impact on functional recovery within the first 3 weeks following injury,a period prone to neuronal remodeling.We demonstrate that,in this time frame,while vGlut2-positive fibers within the gigantocellular and lateral paragigantocellular nuclei rewire significantly following cervical spinal cord injury,vGat-positive fibers are rather unresponsive to injury.We also show that the acute silencing of excitatory axonal fibers which rewire in response to lesions of the spinal cord triggers a worsening of the functional recovery.Using kinematic analysis,we also pinpoint the locomotion features associated with the gigantocellular nucleus or lateral paragigantocellular nucleus during functional recovery.Overall,our study increases the understanding of the role of the gigantocellular and lateral paragigantocellular nuclei during functional recovery following spinal cord injury.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the tim...After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.展开更多
Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,explorin...Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,exploring effective strategies to promote the repair and regeneration of nerve cells after spinal cord injury is crucial for optimizing patient prognosis.The purpose of this paper is to conduct an in-depth review of the pathological changes in nerve cells after spinal cord injury and to present the state of research on the role of exercise training in promoting the repair and regeneration of nerve cells after spinal cord injury.In terms of the intrinsic growth capacity of neurons,disruptions in the dynamic balance between growth cones and the cytoskeleton,the dysregulation of transcription factors,abnormal protein signaling transduction,and altered epigenetic modifications collectively hinder axonal regeneration.Additionally,the microenvironment of neurons undergoes a series of complex changes,initially manifesting as edema,which may be exacerbated by spinal cord ischemia-reperfusion injury,further increasing the extent of nerve cell damage.The abnormal proliferation of astrocytes leads to the formation of glial scars,creating a physical barrier to nerve regeneration.The inflammatory response triggered by the excessive activation of microglia negatively impacts the process of nerve repair.Non-invasive interventions involving exercise training have shown significant potential in promoting nerve repair as part of a comprehensive treatment strategy for spinal cord injury.Specifically,exercise training can reshape the growth cone and cytoskeletal structures of neurons,regulate transcription factor activity,modulate protein signaling pathways,and influence epigenetic modifications,thereby activating the intrinsic repair mechanisms of neurons.Moreover,exercise training can regulate the activation state of astrocytes,optimize the inflammatory response and metabolic processes,promote astrocyte polarization,enhance angiogenesis,reduce glial scar formation,and modulate the expression levels of nerve growth factors.It also effectively helps regulate microglial activation,promotes axonal regeneration,and improves phagocytic function,thereby optimizing the microenvironment for nerve repair.In terms of clinical translation,we summarize the preliminary results of new drug research and development efforts,the development of innovative devices,and the use of exercise training in promoting clinical advancements in nerve repair following spinal cord injury,while considering their limitations and future application prospects.In summary,this review systematically analyzes findings relating to the pathological changes occurring in nerve cells after spinal cord injury and emphasizes the critical role of exercise training in facilitating the repair and regeneration of nerve cells.This work is expected to provide new ideas and methods for the rehabilitation of patients with spinal cord injury.展开更多
Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord inj...Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.展开更多
The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on elimin...The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on eliminating fibrotic scars by blocking(Göritz et al.,2011)or inhibiting(Dias et al.,2018)the generation of scar-forming stromal cells,as well as inducing their migratory defect(Hellal et al.,2011;Ruschel et al.,2015).展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types ...Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types involved in this process,the underlying molecular and cellular mechanisms remain largely unexplored.In this study,we used single-cell RNA sequencing to profile distinct cell populations at different stages of spinal cord injury in zebrafish.Our analysis revealed that multiple subpopulations of neurons showed persistent activation of genes associated with axonal regeneration post injury,while molecular signals promoting growth cone collapse were inhibited.Radial glial cells exhibited significant proliferation and differentiation potential post injury,indicating their intrinsic roles in promoting neurogenesis and axonal regeneration,respectively.Additionally,we found that inflammatory factors rapidly decreased in the early stages following spinal cord injury,creating a microenvironment permissive for tissue repair and regeneration.Furthermore,oligodendrocytes lost maturity markers while exhibiting increased proliferation following injury.These findings demonstrated that the rapid and orderly regulation of inflammation,as well as the efficient proliferation and redifferentiation of new neurons and glial cells,enabled zebrafish to reconstruct the spinal cord.This research provides new insights into the cellular transitions and molecular programs that drive spinal cord regeneration,offering promising avenues for future research and therapeutic strategies.展开更多
Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine tri...Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine triphosphate,ion imbalance,the excessive production of reactive oxygen species,neuroinflammation,and neuronal cell death.Therefore,maintaining an appropriate balance of mitophagy is crucial when treating spinal cord injury,as both excessive and insufficient mitophagy can impede recovery.In this review,we summarize the pathological changes associated with spinal cord injury,the mechanisms of mitophagy,and the direct and indirect relationships between mitophagy and spinal cord injury.We also consider therapeutic approaches that target mitophagy for the treatment of spinal cord injury,including ongoing clinical trials and other innovative therapies,such as use of stem cells,nanomaterials,and small molecule polymers.Finally,we highlight the current challenges facing this field and suggest potential directions for future research.The aim of our review is to provide a theoretical reference for future studies targeting mitophagy in the treatment of spinal cord injury.展开更多
Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and...Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.展开更多
基金supported by Craig H.Neilsen Foundation,Wings for Life Foundation,Canadian Institutes of Health Research,and Fonds de Recherche Québec-Santé(to FB).
文摘Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are incomplete and spare supraspinal pathways,especially those located within the peripheral white matter of the spinal cord,which includes reticulospinal pathways originating from the medullary reticular formation.Whereas there is abundant literature about the motor cortex,its corticospinal pathway,and its capacity to modulate functional recovery after SCI,less is known about the medullary reticular formation and its reticulospinal pathway.
文摘The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).
基金supported by the Belle Carnell Regenerative Neurorehabilitation Fundthe National Institutes of Health(R01NS113935 to CKF)。
文摘Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).
文摘Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.
基金supported by the Irish Research Council under the Government of Ireland Postdoctoral Fellowship Project ID-GOIPD/2023/1431(to AS).
文摘Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).
基金supported by the Joint Funds for the Innovation of Science and Technology,Fujian Province,No.2023Y9233(to HH)the QuanzhouScience and Technology Project,No.2022C036R(to HH)+1 种基金the Science and Technology Bureau of Quanzhou,No.2020CT003(to SL)the Quanzhou MunicipalMedical and Health Guiding Science and Technology Project,No.2023N066S(to YZhou).
文摘Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.
基金supported by Shenzhen Science and Technology Program, No. JCYJ20230807110259002 (to JL)The Seventh Affiliated Hospital of Sun Yat-sen University, No. ZSQYRSFPD0050 (to JL)The Postdoctoral Fellowship Program of CPSF, No. GZC20242074 (to KT)
文摘Oxidative stress significantly contributes to secondary damage after spinal cord injury.Despite its importance,research on oxidative stress in spinal cord injury remains limited.Investigating the expression and regulation of oxidative stress-related genes could enhance the diagnosis and treatment of spinal cord injury.In this study,we analyzed the sequencing data of human blood samples and injured mouse spinal cord tissue that were sourced from GEO databases and identified diagnostic biomarkers associated with the severity of spinal cord injury.We also explored the expression patterns of oxidative stress-related genes,potential regulatory mechanisms,and therapeutic drugs.To validate our findings,we performed immunofluorescence and quantitative polymerase chain reaction to assess gene expression in the injured spinal cord.Our results revealed biomarkers associated with oxidative stress and immune responses across different levels of spinal cord injury in humans.We identified differentially expressed oxidative stress-related genes and key hub genes in injured mouse spinal cord tissue and revealed their temporal expression patterns at both the tissue and single-cell levels.We also clarified the signaling pathways associated with oxidative stress and identified ligand-receptor pairs among various cell types at different time points after injury.Furthermore,we discovered microRNAs,long non-coding RNAs,and transcription factors that regulate these hub genes and revealed their roles in modulating gene expression at various stages after spinal cord injury.We also identified drugs targeting these hub genes.The findings from this study not only aid in identifying diagnostic biomarkers that reflect the severity of spinal cord injury,but also provide insights into the expression dynamics of oxidative stress-related genes.In addition,the study reveals potential regulatory mechanisms and identifies potential drugs to treat patients with spinal cord injury.
基金supported by Grant 3195 from Paralyzed Veterans of America Research Foundation (to BRK)
文摘The inter-related pathological cascades following a traumatic spinal cord injury(tSCI)disrupt multiple cell types and physiological processes.Subsequently,motor and sensory functions are disrupted by breakdowns in cellular interactions and circuitry.Therapeutic interventions seek to modify some aspects of the injury course to enable the re-establishment of functional circuitry.Interventions often target one cell type(e.g.,promoting neuroprotection or neural regeneration)or one process(e.g.,modulating inflammation,affecting astrocytic,microglial,or macrophage responses.)Many axons in the spinal cord are myelinated,and after injury oligodendrocyte death causes demyelination.Promoting remyelination of spared or new axons to re-establish conduction seems a logical choice as a therapeutic target.
基金supported by the National Natural Science Foundation of China,No.82471411(to ZW and TD)the Key Research and DevelopmentProgram of Shaanxi Province,No.2023-ZDLSF-12(to TD).
文摘The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system.After spinal cord injury,autophagic flux within endothelial cells is disrupted,compromising the integrity of the blood-spinal cord barrier.This disruption facilitates extensive infiltration of inflammatory cells,resulting in exacerbated neuroinflammatory responses,neuronal death,and impaired neuronal regeneration.Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function.However,the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated.In this study,we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment.Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice,promoting recovery of hindlimb motor function.Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation,we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway.Additionally,photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier.Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway,thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.
文摘Traumatic spinal cord injury(SCI)is a pathological condition that impairs both sensorimotor and cognitive functions.While research has long focused on understanding the pathophysiology of SCI and developing treatments,only a few studies have investigated the cellular and molecular consequences that occur in the brain after trauma.From the earliest stages,the injury triggers microglial activation,increased neuronal death,and reduced hippocampal neurogenesis in the dentate gyrus.
基金supported by the Deutsche Forschungsgemeinschaft(DFG),TRR274(Project ID 408885537,Sy Nergy,EXC 2145/ID 390857198,to FMB)。
文摘The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory fibers.While the reticulospinal tract has been shown to be particularly prone to axonal growth and plasticity following injuries of the spinal cord,the differential capacities of excitatory and inhibitory fibers for plasticity remain unclear.As adaptive axonal plasticity involves a sophisticated interplay between excitatory and inhibitory input,we investigated in this study the plastic potential of glutamatergic(vGlut2)and GABAergic(vGat)fibers originating from the gigantocellular nucleus and the lateral paragigantocellular nucleus,two nuclei important for locomotor function.Using a combination of viral tracing,chemogenetic silencing,and AI-based kinematic analysis,we investigated plasticity and its impact on functional recovery within the first 3 weeks following injury,a period prone to neuronal remodeling.We demonstrate that,in this time frame,while vGlut2-positive fibers within the gigantocellular and lateral paragigantocellular nuclei rewire significantly following cervical spinal cord injury,vGat-positive fibers are rather unresponsive to injury.We also show that the acute silencing of excitatory axonal fibers which rewire in response to lesions of the spinal cord triggers a worsening of the functional recovery.Using kinematic analysis,we also pinpoint the locomotion features associated with the gigantocellular nucleus or lateral paragigantocellular nucleus during functional recovery.Overall,our study increases the understanding of the role of the gigantocellular and lateral paragigantocellular nuclei during functional recovery following spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the National Key Research and Development Program of China,No.2023YFC3603705(to DX)the National Natural Science Foundation of China,No.82302866(to YZ).
文摘After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.
基金supported by the National Natural Science Foundation of China,No.81641048Research Project of Yan’an University,No.2023JBZR-011(both to LZ).
文摘Spinal cord injury is a severe neurological condition characterized by the permanent loss of nerve cell function and a failure in neural circuit reconstruction-key factors contributing to disability.Therefore,exploring effective strategies to promote the repair and regeneration of nerve cells after spinal cord injury is crucial for optimizing patient prognosis.The purpose of this paper is to conduct an in-depth review of the pathological changes in nerve cells after spinal cord injury and to present the state of research on the role of exercise training in promoting the repair and regeneration of nerve cells after spinal cord injury.In terms of the intrinsic growth capacity of neurons,disruptions in the dynamic balance between growth cones and the cytoskeleton,the dysregulation of transcription factors,abnormal protein signaling transduction,and altered epigenetic modifications collectively hinder axonal regeneration.Additionally,the microenvironment of neurons undergoes a series of complex changes,initially manifesting as edema,which may be exacerbated by spinal cord ischemia-reperfusion injury,further increasing the extent of nerve cell damage.The abnormal proliferation of astrocytes leads to the formation of glial scars,creating a physical barrier to nerve regeneration.The inflammatory response triggered by the excessive activation of microglia negatively impacts the process of nerve repair.Non-invasive interventions involving exercise training have shown significant potential in promoting nerve repair as part of a comprehensive treatment strategy for spinal cord injury.Specifically,exercise training can reshape the growth cone and cytoskeletal structures of neurons,regulate transcription factor activity,modulate protein signaling pathways,and influence epigenetic modifications,thereby activating the intrinsic repair mechanisms of neurons.Moreover,exercise training can regulate the activation state of astrocytes,optimize the inflammatory response and metabolic processes,promote astrocyte polarization,enhance angiogenesis,reduce glial scar formation,and modulate the expression levels of nerve growth factors.It also effectively helps regulate microglial activation,promotes axonal regeneration,and improves phagocytic function,thereby optimizing the microenvironment for nerve repair.In terms of clinical translation,we summarize the preliminary results of new drug research and development efforts,the development of innovative devices,and the use of exercise training in promoting clinical advancements in nerve repair following spinal cord injury,while considering their limitations and future application prospects.In summary,this review systematically analyzes findings relating to the pathological changes occurring in nerve cells after spinal cord injury and emphasizes the critical role of exercise training in facilitating the repair and regeneration of nerve cells.This work is expected to provide new ideas and methods for the rehabilitation of patients with spinal cord injury.
基金funded by the National Natural Science Foundation of China,No.82271395(to GL),the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030073(to GL)the grants from University of Macao Research Committee,China,No.MYRG2022-00074-ICMS(to CTV)Guangzhou Science and Technology Program Project,No.2025A04J4740(to GL).
文摘Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.
文摘The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on eliminating fibrotic scars by blocking(Göritz et al.,2011)or inhibiting(Dias et al.,2018)the generation of scar-forming stromal cells,as well as inducing their migratory defect(Hellal et al.,2011;Ruschel et al.,2015).
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
基金supported by the Jiangsu Province Traditional Chinese Medicine Technology Development Plan Project,Nos.MS2023113(to JC),MS2022090Young and Middle-aged Academic Leaders of Jiangsu Qing-Lan Project(to GL).
文摘Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types involved in this process,the underlying molecular and cellular mechanisms remain largely unexplored.In this study,we used single-cell RNA sequencing to profile distinct cell populations at different stages of spinal cord injury in zebrafish.Our analysis revealed that multiple subpopulations of neurons showed persistent activation of genes associated with axonal regeneration post injury,while molecular signals promoting growth cone collapse were inhibited.Radial glial cells exhibited significant proliferation and differentiation potential post injury,indicating their intrinsic roles in promoting neurogenesis and axonal regeneration,respectively.Additionally,we found that inflammatory factors rapidly decreased in the early stages following spinal cord injury,creating a microenvironment permissive for tissue repair and regeneration.Furthermore,oligodendrocytes lost maturity markers while exhibiting increased proliferation following injury.These findings demonstrated that the rapid and orderly regulation of inflammation,as well as the efficient proliferation and redifferentiation of new neurons and glial cells,enabled zebrafish to reconstruct the spinal cord.This research provides new insights into the cellular transitions and molecular programs that drive spinal cord regeneration,offering promising avenues for future research and therapeutic strategies.
基金supported by the National Natural Science Foundation of China,Nos.82371389,82071382(to MZ)the Priority Academic Program Development of Jiangsu Higher Education Institutions,PAPD(to MZ)+4 种基金Jiangsu Maternal and Child Health Research Key Project,No.F202013(to HS)Jiangsu 333 High Level Talent Training Project,2022(to HS)Gusu District Health Talent Training Project,No.2024145(to HS)Suzhou BenQ Medical Center Project,No.H220918(to MZ)Undergraduate Training Program for Innovation and Entrepreneurship,Soochow University,No.202410285091Z(to MZ)。
文摘Mitophagy is closely associated with the pathogenesis of secondary spinal cord injury.Abnormal mitophagy may contribute significantly to secondary spinal cord injury,leading to the impaired production of adenosine triphosphate,ion imbalance,the excessive production of reactive oxygen species,neuroinflammation,and neuronal cell death.Therefore,maintaining an appropriate balance of mitophagy is crucial when treating spinal cord injury,as both excessive and insufficient mitophagy can impede recovery.In this review,we summarize the pathological changes associated with spinal cord injury,the mechanisms of mitophagy,and the direct and indirect relationships between mitophagy and spinal cord injury.We also consider therapeutic approaches that target mitophagy for the treatment of spinal cord injury,including ongoing clinical trials and other innovative therapies,such as use of stem cells,nanomaterials,and small molecule polymers.Finally,we highlight the current challenges facing this field and suggest potential directions for future research.The aim of our review is to provide a theoretical reference for future studies targeting mitophagy in the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.82002645China Postdoctoral Science Foundation,No.2022M722321Jiangsu Funding Program for Excellent Postdoctoral Talent,No.2022ZB552(all to YH)。
文摘Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.
