There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progre...There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.展开更多
The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the C...The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.展开更多
Mammalian adult central nerve system （CNS） injuries are devastating because of the intrinsic difficulties for effective neuronal regeneration. The greatest problem to be overcome for CNS recovery is the poor regener...Mammalian adult central nerve system （CNS） injuries are devastating because of the intrinsic difficulties for effective neuronal regeneration. The greatest problem to be overcome for CNS recovery is the poor regeneration of neurons and myelin-forming cells, oligodendrocytes. Endogenous neural progenitors and transplanted exogenous neuronal stem cells can be the source for neuronal regeneration. However, because of the harsh local microenvironment, they usually have very low efficacy for functional neural regeneration which cannot compensate for the loss of neurons and oligodendrocytes. Glial cells （including astrocytes, microglia, oligodendrocytes and NG2 glia） are the majority of cells in CNS that provide support and protection for neurons. Inside the local microenvironment, glial cells largely influence local and transplanted neural stem cells survival and fates. This review critically analyzes current finding of the roles of glial cells in CNS regeneration, and highlights strategies for regulating glial cells＇ behavior to create a permissive microenvironment for neuronal stem cells.展开更多
Traumatic injury to the adult mammalian central nervous system（CNS） leads to complex cellular responses. Among them, the scar tissue formed is generally recognized as a major obstacle to CNS repair, both by the prod...Traumatic injury to the adult mammalian central nervous system（CNS） leads to complex cellular responses. Among them, the scar tissue formed is generally recognized as a major obstacle to CNS repair, both by the production of inhibitory molecules and by the physical impedance of axon regrowth. Therefore, scar-modulating treatments have become a leading therapeutic intervention for CNS injury. To date, a variety of biological and pharmaceutical treatments, targeting scar modulation, have been tested in animal models of CNS injury, and a few are likely to enter clinical trials. In this review, we summarize current knowledge of the scar-modulating treatments according to their specific aims：（1） inhibition of glial and fibrotic scar formation, and（2） blockade of the production of scar-associated inhibitory molecules. The removal of existing scar tissue is also discussed as a treatment of choice. It is believed that only a combinatorial strategy is likely to help eliminate the detrimental effects of scar tissue on CNS repair.展开更多
Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising...Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.展开更多
The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank...The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank regeneration of injured axons. Here, we argue that sprouting of uninjured axons, an innate repair mech- anism of the CNS, might be more amenable to modulation in order to promote functional repair. Extrinsic inhibitors of axonal growth modulate axon sprouting after injury and may serve as the first group of therapeutic targets to promote functional repair.展开更多
The central nervous system （CNS） contains the two most important organs, the brain and spinal cord, for the orchestration of the mental and physical activities of life. Because of its importance, the human body has ...The central nervous system （CNS） contains the two most important organs, the brain and spinal cord, for the orchestration of the mental and physical activities of life. Because of its importance, the human body has evolved barrier systems to protect CNS tissue from the external environment. This barrier is a membrane composed of tightly apposed cells and is selectively permeable to specific molecules by way of membrane transporters.展开更多
After central nervous system（CNS）injury,a pro-inflammatory,innate immune response contributes to permanently lost neuronal function by promoting changes in the micro-environment and extracellular matrix（ECM）that l...After central nervous system（CNS）injury,a pro-inflammatory,innate immune response contributes to permanently lost neuronal function by promoting changes in the micro-environment and extracellular matrix（ECM）that lead to CNS neuronal degeneration and death and permanent scarring.展开更多
文摘There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.
基金supported by the Finnish Funding Agency for Innovation Tekes,Academy of FinlandSigrid Jusélius Foundation
文摘The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.
基金supported in part by the Nippon Dental University Research Project 4 Grant and Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research(26861689)
文摘Mammalian adult central nerve system （CNS） injuries are devastating because of the intrinsic difficulties for effective neuronal regeneration. The greatest problem to be overcome for CNS recovery is the poor regeneration of neurons and myelin-forming cells, oligodendrocytes. Endogenous neural progenitors and transplanted exogenous neuronal stem cells can be the source for neuronal regeneration. However, because of the harsh local microenvironment, they usually have very low efficacy for functional neural regeneration which cannot compensate for the loss of neurons and oligodendrocytes. Glial cells （including astrocytes, microglia, oligodendrocytes and NG2 glia） are the majority of cells in CNS that provide support and protection for neurons. Inside the local microenvironment, glial cells largely influence local and transplanted neural stem cells survival and fates. This review critically analyzes current finding of the roles of glial cells in CNS regeneration, and highlights strategies for regulating glial cells＇ behavior to create a permissive microenvironment for neuronal stem cells.
基金supported by grants from the National Basic Research Development Program (973 Program) of China (2014CB542202)National High-Technology Research Program (863 Program) of China (2012AA020502)+1 种基金the National Natural Science Foundation of China (81130080)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions,Jiangsu Province,China
文摘Traumatic injury to the adult mammalian central nervous system（CNS） leads to complex cellular responses. Among them, the scar tissue formed is generally recognized as a major obstacle to CNS repair, both by the production of inhibitory molecules and by the physical impedance of axon regrowth. Therefore, scar-modulating treatments have become a leading therapeutic intervention for CNS injury. To date, a variety of biological and pharmaceutical treatments, targeting scar modulation, have been tested in animal models of CNS injury, and a few are likely to enter clinical trials. In this review, we summarize current knowledge of the scar-modulating treatments according to their specific aims：（1） inhibition of glial and fibrotic scar formation, and（2） blockade of the production of scar-associated inhibitory molecules. The removal of existing scar tissue is also discussed as a treatment of choice. It is believed that only a combinatorial strategy is likely to help eliminate the detrimental effects of scar tissue on CNS repair.
基金supported by the National Natural Science Foundation of China(No.81974210)the Science and Technology Planning Project of Guangdong Province,China(No.2020A0505100045)the Natural Science Foundation of Guangdong Province(No.2019A1515010671),all to CKT.
文摘Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.
基金supported by grants from NIH/ NINDS (R01NS054734)the California Institute for Regenerative Medicinethe Craig H. Neilsen Foundation and Wings for Life Spinal Cord Research Foundation
文摘The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank regeneration of injured axons. Here, we argue that sprouting of uninjured axons, an innate repair mech- anism of the CNS, might be more amenable to modulation in order to promote functional repair. Extrinsic inhibitors of axonal growth modulate axon sprouting after injury and may serve as the first group of therapeutic targets to promote functional repair.
基金supported by the Global Research Laboratory Program(2011-0021874)Brain Korea 21 Program,the Global Core Research Center(GCRC)Program(20110030001)through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and Future Planning(MSIP)
文摘The central nervous system （CNS） contains the two most important organs, the brain and spinal cord, for the orchestration of the mental and physical activities of life. Because of its importance, the human body has evolved barrier systems to protect CNS tissue from the external environment. This barrier is a membrane composed of tightly apposed cells and is selectively permeable to specific molecules by way of membrane transporters.
基金funding from the Department of Defense office of the Congressionally Directed Medical Research Programs and the Clinical and Rehabilitative Medicine Research Program (MBS,MR130444)Competitive Medical Research Fund,University of Pittsburgh (MBS),Pennsylvania Lions Sight Conservation & Eye Research Foundation (MBS),Sterling Lions Club of Pennsylvania and Dance for Sight (MBS),Start-up funds,Department of Ophthalmology,University of Pittsburgh (MBS)+1 种基金National Institutes of Health CORE Grant P30 EY008098Eye and Ear Foundation of Pittsburgh,PA,Unrestricted Grant from Research to Prevent Blindness,New York,NY
文摘After central nervous system（CNS）injury,a pro-inflammatory,innate immune response contributes to permanently lost neuronal function by promoting changes in the micro-environment and extracellular matrix（ECM）that lead to CNS neuronal degeneration and death and permanent scarring.
