Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is prop...Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region.These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF,GDNF,and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury.Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.展开更多
Graphene and graphene-based materials have the ability to induce stem cells to differentiate into neurons,which is necessary to overcome the current problems faced in the clinical treatment of spinal cord injury.This ...Graphene and graphene-based materials have the ability to induce stem cells to differentiate into neurons,which is necessary to overcome the current problems faced in the clinical treatment of spinal cord injury.This review summarizes the advantages of graphene and graphene-based materials(in particular,composite materials)in axonal repair after spinal cord injury.These materials have good histocompatibility,and mechanical and adsorption properties that can be targeted to improve the environment of axonal regeneration.They also have good conductivity,which allows them to make full use of electrical nerve signal stimulation in spinal cord tissue to promote axonal regeneration.Furthermore,they can be used as carriers of seed cells,trophic factors,and drugs in nerve tissue engineering scaffolds to provide a basis for constructing a local microenvironment after spinal cord injury.However,to achieve clinical adoption of graphene and graphene-based materials for the repair of spinal cord injury,further research is needed to reduce their toxicity.展开更多
Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence ...Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2(ALDH2),a key oxidoreductase and powerful endogenous anti-aldehyde machinery,is likely important for protecting neurons from aldehydesmediated degeneration.Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator(Alda-1),we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2.Over an acute 2 day period post injury,we found that ALDH2 expression was significantly lowered post-SCI,but not so in rats given Alda-1.This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction,which was revealed in co-immunoprecipitation experiments.We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord,and reduced cyst pathology.In addition,Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI.Finally,ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure.It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.All animal work was approved by Purdue Animal Care and Use Committee(approval No.1111000095)on January 1,2021.展开更多
基金supported by a grant from the Russian Science Foundation,No. 16-15-00010 (to RRI)funded by government assignment for FRC Kazan Scientific Center of RAS
文摘Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region.These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF,GDNF,and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury.Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.
基金supported by the Lanzhou Talent Innovation and Entrepreneurship Project,No.2020-RC-40(to XXW and YBL)Cuiying Scientific Training Program for Undergraduates of Lanzhou University Second Hospital,Nos.CYXZ2020-03,CYXZ2021-01(both to YBL).
文摘Graphene and graphene-based materials have the ability to induce stem cells to differentiate into neurons,which is necessary to overcome the current problems faced in the clinical treatment of spinal cord injury.This review summarizes the advantages of graphene and graphene-based materials(in particular,composite materials)in axonal repair after spinal cord injury.These materials have good histocompatibility,and mechanical and adsorption properties that can be targeted to improve the environment of axonal regeneration.They also have good conductivity,which allows them to make full use of electrical nerve signal stimulation in spinal cord tissue to promote axonal regeneration.Furthermore,they can be used as carriers of seed cells,trophic factors,and drugs in nerve tissue engineering scaffolds to provide a basis for constructing a local microenvironment after spinal cord injury.However,to achieve clinical adoption of graphene and graphene-based materials for the repair of spinal cord injury,further research is needed to reduce their toxicity.
基金supported by a grant from National Institute of Neurological Disorders and Stroke R21(No.1R21NS115094-01)。
文摘Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2(ALDH2),a key oxidoreductase and powerful endogenous anti-aldehyde machinery,is likely important for protecting neurons from aldehydesmediated degeneration.Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator(Alda-1),we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2.Over an acute 2 day period post injury,we found that ALDH2 expression was significantly lowered post-SCI,but not so in rats given Alda-1.This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction,which was revealed in co-immunoprecipitation experiments.We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord,and reduced cyst pathology.In addition,Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI.Finally,ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure.It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.All animal work was approved by Purdue Animal Care and Use Committee(approval No.1111000095)on January 1,2021.
