Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as...Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years.Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.展开更多
Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is inv...Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.展开更多
Spinal cord injury triggers leukocyte mobilization from the peripheral circulation to the injury site,exacerbating spinal cord damage.Simultaneously,bone marrow hematopoietic stem cells(HSCs)and splenic leukocytes rap...Spinal cord injury triggers leukocyte mobilization from the peripheral circulation to the injury site,exacerbating spinal cord damage.Simultaneously,bone marrow hematopoietic stem cells(HSCs)and splenic leukocytes rapidly mobilize to replenish the depleted peripheral blood leukocyte pool.However,current treatments for spinal cord injuries overlook interventions targeting peripheral immune organs and tissues,highlighting the need to develop novel drugs capable of effectively regulating peripheral immunity and treating spinal cord injuries.In this study,we designed,synthesized,and characterized novel Ejiao carbon dots(EJCDs)that inhibit myeloid cell proliferation and peripheral migration by promoting HSC self-renewal,and distinct differentiation into erythroid progenitors in vitro and in vivo.Additionally,EJCDs attenuate the immune response in the spleen,leukocytes’reservoir,following spinal cord injury by diminishing the local infiltration of monocytes and macrophages while promoting motor function recovery.These effects are mediated through the downregulation of CCAAT enhancer binding protein-βexpression in the spleen and the upregulation of FZD4 protein expression in LinSca-1+c-kit+cells(LSKs)within the bone marrow.Our findings demonstrate that EJCDs effectively reduce myeloid cell infiltration post-spinal cord injury and promote neurological recovery,making them promising therapeutic candidates for treating spinal cord injuries.展开更多
Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we use...Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we used a single-cell RNA sequencing dataset to create a comprehensive profile of the diverse cell types in the dorsal root ganglia and spinal cord of a mid-thoracic contusion injury model in cynomolgus monkeys.Cell communication analysis indicated that specific signaling events among various dorsal root ganglia cell types occur in response to spinal cord injury.Single-cell analysis using dimensionality reduction clustering identified distinct molecular signatures for nine cell types,including macrophage subpopulations,and differential gene expression profiles between dorsal root ganglia cells and spinal cord cells following spinal cord injury.The macrophage subpopulations were categorized into 11 clusters(MC0-MC10)based on differentially expressed genes,with the top 10 genes being ABCA6,RBMS3,EBF1,LAMA4,ANTXR2,LAMA2,SOX5,FOXP2,GHR,and APOD.MC0,MC1,and MC2 constituted the predominant macrophage populations.MC4,MC6,and MC9 were nearly absent in the spinal cord,but exhibited significant increases in the dorsal root ganglia post-spinal cord injury.Notably,these subpopulations possess a strong capacity for regulating axonal regeneration.The developmental progression of dorsal root ganglia macrophages after spinal cord injury was elucidated using cell trajectory and pseudo-time analyses.Genes such as EBF1(MC6 and MC9 marker),RBMS3(MC6 and MC9 marker),and ABCA6(MC6 marker)showed high expression levels in the critical pathways of macrophage function.Through ligand-receptor pair analysis,we determined that the effects of macrophages on microglia are predominantly mediated through interaction pairs(e.g.,SPP1-CD44,LAMC1-CD44,and FN1-CD44),potentially facilitating specific cellular communications within the immune microenvironment.The single-cell RNA sequencing dataset used in this study represents the first comprehensive transcriptional analysis of the dorsal root ganglia after spinal cord injury in cynomolgus monkeys,encompassing nearly all cell types within the dorsal root ganglia region.Using this dataset,we evaluated diverse subtypes of macrophages in the post-spinal cord injury dorsal root ganglia area and examined the signaling pathways that facilitate interactions among immune response-related macrophages in the dorsal root ganglia.Findings from this study provide a theoretical basis for understanding how the immune microenvironment influences the regenerative capacity of dorsal root ganglia neurons after spinal cord injury and offer novel insights into the complex processes underlying the pathobiology of spinal cord injury.展开更多
Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal rege...Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury,as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier.To develop an effective non-invasive treatment strategy for SCI in clinic,we generated an autologous plasma exosome(AP-EXO)based biological scaffold where AP-EXO was loaded with neuron targeting peptide(RVG)and growth-facilitating peptides(ILP and ISP).This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment,thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice.More importantly,in ex vivo,human plasma exosomes(HP-EXO)loaded with combinatory peptides of RVG,ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice.Combining the efficacy and safety,the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI.It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.展开更多
基金the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100).
文摘Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years.Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.
基金National Natural Science Foundation of China,No.81972074 (to XY)Natural Science Foundation of Tianjin,No.19JCZDJC34900 (to XY)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100 (to SF)。
文摘Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.
基金supported by grants from the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100)the National Natural Science of China(81930070,82102671)+3 种基金Tianjin Key Medical Discipline(Specialty)Construct Project(TJYXZDXK-027A)Tianjin Science and Technology Project(21JCZDJC01100)the Beijing-Tianjin-Hebei Basic Research Cooperation Project(J230012)Taishan Scholar Young Expert(tsqnz20221168).
文摘Spinal cord injury triggers leukocyte mobilization from the peripheral circulation to the injury site,exacerbating spinal cord damage.Simultaneously,bone marrow hematopoietic stem cells(HSCs)and splenic leukocytes rapidly mobilize to replenish the depleted peripheral blood leukocyte pool.However,current treatments for spinal cord injuries overlook interventions targeting peripheral immune organs and tissues,highlighting the need to develop novel drugs capable of effectively regulating peripheral immunity and treating spinal cord injuries.In this study,we designed,synthesized,and characterized novel Ejiao carbon dots(EJCDs)that inhibit myeloid cell proliferation and peripheral migration by promoting HSC self-renewal,and distinct differentiation into erythroid progenitors in vitro and in vivo.Additionally,EJCDs attenuate the immune response in the spleen,leukocytes’reservoir,following spinal cord injury by diminishing the local infiltration of monocytes and macrophages while promoting motor function recovery.These effects are mediated through the downregulation of CCAAT enhancer binding protein-βexpression in the spleen and the upregulation of FZD4 protein expression in LinSca-1+c-kit+cells(LSKs)within the bone marrow.Our findings demonstrate that EJCDs effectively reduce myeloid cell infiltration post-spinal cord injury and promote neurological recovery,making them promising therapeutic candidates for treating spinal cord injuries.
基金supported by the Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)the National Key Research andDevelopment Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+2 种基金Tianjin Natural Science Foundation’s Youth Project for DiverseInvestments,No.21JCQNJC01300(to BF)the National Natural Science Foundation of China(Youth Program),No.82102563(to BF)Tianjin Major Science andTechnology Special Projects and Engineering Projects,No.21ZXJBSY00080(to YR).
文摘Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we used a single-cell RNA sequencing dataset to create a comprehensive profile of the diverse cell types in the dorsal root ganglia and spinal cord of a mid-thoracic contusion injury model in cynomolgus monkeys.Cell communication analysis indicated that specific signaling events among various dorsal root ganglia cell types occur in response to spinal cord injury.Single-cell analysis using dimensionality reduction clustering identified distinct molecular signatures for nine cell types,including macrophage subpopulations,and differential gene expression profiles between dorsal root ganglia cells and spinal cord cells following spinal cord injury.The macrophage subpopulations were categorized into 11 clusters(MC0-MC10)based on differentially expressed genes,with the top 10 genes being ABCA6,RBMS3,EBF1,LAMA4,ANTXR2,LAMA2,SOX5,FOXP2,GHR,and APOD.MC0,MC1,and MC2 constituted the predominant macrophage populations.MC4,MC6,and MC9 were nearly absent in the spinal cord,but exhibited significant increases in the dorsal root ganglia post-spinal cord injury.Notably,these subpopulations possess a strong capacity for regulating axonal regeneration.The developmental progression of dorsal root ganglia macrophages after spinal cord injury was elucidated using cell trajectory and pseudo-time analyses.Genes such as EBF1(MC6 and MC9 marker),RBMS3(MC6 and MC9 marker),and ABCA6(MC6 marker)showed high expression levels in the critical pathways of macrophage function.Through ligand-receptor pair analysis,we determined that the effects of macrophages on microglia are predominantly mediated through interaction pairs(e.g.,SPP1-CD44,LAMC1-CD44,and FN1-CD44),potentially facilitating specific cellular communications within the immune microenvironment.The single-cell RNA sequencing dataset used in this study represents the first comprehensive transcriptional analysis of the dorsal root ganglia after spinal cord injury in cynomolgus monkeys,encompassing nearly all cell types within the dorsal root ganglia region.Using this dataset,we evaluated diverse subtypes of macrophages in the post-spinal cord injury dorsal root ganglia area and examined the signaling pathways that facilitate interactions among immune response-related macrophages in the dorsal root ganglia.Findings from this study provide a theoretical basis for understanding how the immune microenvironment influences the regenerative capacity of dorsal root ganglia neurons after spinal cord injury and offer novel insights into the complex processes underlying the pathobiology of spinal cord injury.
基金This work was supported by the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100),ChinaNational Natural Science Foundation of China(81930070)+3 种基金National Natural Science Foundation of China(82102560)the Natural Science Foundation of Shandong Province,China(ZR2021QH097)the No.69 General Fund of China Postdoctoral Science Foundation(2021M691936)Talent project of Shandong University(22480082063100),China.
文摘Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury,as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier.To develop an effective non-invasive treatment strategy for SCI in clinic,we generated an autologous plasma exosome(AP-EXO)based biological scaffold where AP-EXO was loaded with neuron targeting peptide(RVG)and growth-facilitating peptides(ILP and ISP).This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment,thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice.More importantly,in ex vivo,human plasma exosomes(HP-EXO)loaded with combinatory peptides of RVG,ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice.Combining the efficacy and safety,the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI.It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.
