Long non-coding RNAs(lncRNAs)are abundantly expressed in the central nervous system and exert a critical role in gene regulation via multiple biological processes.To uncover the functional significance and molecular m...Long non-coding RNAs(lncRNAs)are abundantly expressed in the central nervous system and exert a critical role in gene regulation via multiple biological processes.To uncover the functional significance and molecular mechanisms of lncRNAs in spinal cord injury(SCI),the expression signatures of lncRNAs were profiled using RNA sequencing(RNA-seq)technology in a Sprague-Dawley rat model of the 10th thoracic vertebra complete transection SCI.Results showed that 116 of 14,802 detected lncRNAs were differentially expressed,among which 16—including eight up-regulated(H19,Vof16,Hmox2-ps1,LOC100910973,Ybx1-ps3,Nnat,Gcgr,LOC680254)and eight down-regulated(Rmrp,Terc,Ngrn,Ppp2r2b,Cox6a2,Rpl37a-ps1,LOC360231,Rpph1)—demonstrated fold changes>2 in response to transection SCI.A subset of these RNA-seq results was validated by quantitative real-time PCR.The levels of 821 mRNAs were also significantly altered post-SCI;592 mRNAs were up-regulated and 229 mRNAs were down-regulated by more than 2-fold.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses showed that differentially expressed mRNAs were related to GO biological processes and molecular functions such as injury and inflammation response,wound repair,and apoptosis,and were significantly enriched in 15 KEGG pathways,including cell phagocytosis,tumor necrosis factor alpha pathway,and leukocyte migration.Our results reveal the expression profiles of lncRNAs and mRNAs in the rat spinal cord of a complete transection model,and these differentially expressed lncRNAs and mRNAs represent potential novel targets for SCI treatment.We suggest that lncRNAs may play an important role in the early immuno-inflammatory response after spinal cord injury.This study was approved by the Administration Committee of Experimental Animals,Guangdong Province,China.展开更多
OBJECTIVE： To evaluate the effects of olfactory ensheathing cell transplantation on functional recovery of rats with complete spinal cord transection. DATA SOURCES： A computer-based online search of Medline （1989-2...OBJECTIVE： To evaluate the effects of olfactory ensheathing cell transplantation on functional recovery of rats with complete spinal cord transection. DATA SOURCES： A computer-based online search of Medline （1989-2013）, Embase （1989- 2013）, Cochrane library （1989-2013）, Chinese Biomedical Literature Database （1989-2013）, China National Knowledge Infrastructure （1989-2013）, VIP （1989-2013）, Wanfang databases （1989-2013） and Chinese Clinical Trial Register was conducted to collect randomized controlled trial data regarding olfactory ensheathing cell transplantation for the treatment of complete spinal cord transection in rats. SELECTION CRITERIA： Randomized controlled trials investigating olfactory ensheathing cell transplantation and other transplantation methods for promoting neurological functional recov- ery of rats with complete spinal cord transection were included in the analysis. Meta analysis was conducted using RevMan 4.2.2 software. MAIN OUTCOME MEASURES： Basso, Beattie and Bresnahan scores of rats with complete spinal cord transection were evaluated in this study. RESULTS： Six randomized controlled trials with high quality methodology were included. Meta analysis showed that Basso, Beattie and Bresnahan scores were significantly higher in the olfacto- ry ensheathing cell transplantation group compared with the control group （WMD = 3.16, 95% （21 （1.68, 4.65）; P 〈 0.00001）. CONCLUSION： Experimental studies have shown that olfactory ensheathing cell transplantation can promote the functional recovery of motor nerves in rats with complete spinal cord transection.展开更多
Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previou...Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete injury.However,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental importance.The reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural regeneration.Thus,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies.First,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further investigation.Here,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.展开更多
Collagen scaffolds possess a three-dimensional porous structure that provides sufficient space for cell growth and proliferation,the passage of nutrients and oxygen,and the discharge of metabolites.In this study,a por...Collagen scaffolds possess a three-dimensional porous structure that provides sufficient space for cell growth and proliferation,the passage of nutrients and oxygen,and the discharge of metabolites.In this study,a porous collagen scaffold with axially-aligned luminal conduits was prepared.In vitro biocompatibility analysis of the collagen scaffold revealed that it enhances the activity of neural stem cells and promotes cell extension,without affecting cell differentiation.The collagen scaffold loaded with neural stem cells improved the hindlimb motor function in the rat model of T8 complete transection and promoted nerve regeneration.The collagen scaffold was completely degraded in vivo within 5 weeks of implantation,exhibiting good biodegradability.Rectal temperature,C-reactive protein expression and CD68 staining demonstrated that rats with spinal cord injury that underwent implantation of the collagen scaffold had no notable inflammatory reaction.These findings suggest that this novel collagen scaffold is a good carrier for neural stem cell transplantation,thereby enhancing spinal cord repair following injury.This study was approved by the Animal Ethics Committee of Nanjing Drum Tower Hospital(the Affiliated Hospital of Nanjing University Medical School),China(approval No.2019AE02005)on June 15,2019.展开更多
BACKGROUND:The establishment of a rat model of complete transected spinal cord injury lacks technological specifications.The current models lack concordance and reliability,and the death rate of the experimental anima...BACKGROUND:The establishment of a rat model of complete transected spinal cord injury lacks technological specifications.The current models lack concordance and reliability,and the death rate of the experimental animals is high.Therefore,there is a great need for a reliable model to apply clinical applications of therapy.OBJECTIVE:To construct a rat model of complete transected spinal cord injury characterized by stability,reproducibility,and a high animal survival rate.DESIGN:Completely randomized controlled study.SETTING:Department of Neurosurgery,Xiangya Hospital of Central South University.MATERIALS:Fifty-five healthy specific pathogen free grade adult female Sprague Dawley rats were provided by the Experimental Animal Department,Xiangya Medical College,Central South University.Olympus BX51 imaging collecting analytic system was provided by Olympus Company,Japan;and SEN-7203 Nihon-Kohden electrical stimulator by Nihon Kohden,Japan.METHODS:This study was performed at the Laboratory of Neurosurgery,Xiangya Hospital of Central South University from April to June 2006.Experimental grouping:55 rats were randomly divided into model group(n=40)and sham surgery group(n=15).In the model group,a self-made sliver hook was passed through the ventral side to support the spinal cord at the T12 segment and to shear it off.A complete transected spinal cord,2 mm in length,was resected.In the sham surgery group,the spinal cord was identically exposed.The dura mater of the spinal cord was cut open,but the spinal cord was not damaged.MAIN OUTCOME MEASURES:Histopathological changes after spinal cord injury at L2 segment were observed subsequent to hematoxylin and eosin staining under optical microscopy.Olympus BX51 imaging collecting analytic system was used to count spinal cord ventral horn neurons.Motor function of rat hindlimb was evaluated with the Basso,Beattie and Bresnahan(BBB)scale.Paraplegia was evaluated as 0 point,and complete normality as 21 points.Somatosensory-evoked potential was measured using Nihon-Kohden electric stimulator at 21 days post-operation.RESULTS:A total of 82%(33/40)rats survived longer than 30 days after modeling.Pathological changes of spinal cord tissue:degenerative and necrotic pathological changes appeared in the model group after surgery;for example,neuronal swelling,chromatinolysis,and karyopyknosis.The spinal cord in the sham surgery group displayed mild edema 24 hours after surgery,gradually recovering to normal levels.Quantification of spinal cord ventral horn neurons:the number of spinal cord ventral horn neurons in the model group was less than in the sham surgery group at 24 hours,as well as 7 and 21 days after surgery(P〈0.01);while,the number at 7 and 21 days after surgery decreased compared to 24 hours after surgery(P〈0.01).Motor function changes:Rats in the sham operation group moved lightly abnormally following anesthesia recovery and then moved normally 7 days after surgery.BBB scores in the model group were less than in the sham surgery group 21 days after surgery(P〈0.01).BBB scores of both lower extremities increased slightly 7 days after surgery(P〈0.01);however,voluntary motor function of both lower extremities was still not recovered 30 days after surgery.Changes of somatosensory-evoked potential:wave form of somatosensory-evoked potential was normal in the sham surgery group 21 days after surgery,but recovered wave form was not recorded in the model group.CONCLUSION:Results from spinal cord histopathology,cytology,motor function,and somatosensory-evoked potential suggested that the complete transected spinal cord injury model in this study was stable,reliable,and reproducible.Furthermore,the survival rate of experimental animals was high.展开更多
Traumatic spinal cord injury (SCI) usually results in devastating neurologic deficits and disability. In the United States,approximately 12,500 new cases are reported each year, while an estimated 100,000–140,000 new...Traumatic spinal cord injury (SCI) usually results in devastating neurologic deficits and disability. In the United States,approximately 12,500 new cases are reported each year, while an estimated 100,000–140,000 new cases occur every year in China (National Spinal Cord Injury Statistical Center, 2016).Spinal cord injuries are highly disabling and primarily affect young adults, and therefore create great psychological and financial burden on the affected individuals and their families.展开更多
Millions of patients and their caretakers live and deal with the devastating consequences of spinal cord injury(SCI)worldwide.Despite outstanding advances in the field to both understand and tackle these pathologies,a...Millions of patients and their caretakers live and deal with the devastating consequences of spinal cord injury(SCI)worldwide.Despite outstanding advances in the field to both understand and tackle these pathologies,a cure for SCI patients,with their peculiar characteristics,is still a mirage.One of the most promising therapeutic strategies to date for these patients involves the use of epidural electrical stimulation.In this context,electrically active materials such as graphene and its derivates become particularly interesting.Indeed,solid evidence of their capacity to closely interact with neural cells and networks is growing.Encouraged by previous findings in our laboratory on the exploration of 3D porous reduced graphene oxide(rGO)scaffolds in chronic cervical hemisected rats(C6),herein we report their neuro-reparative properties when chronically implanted in complete transected rats(T9-T10),in which no preserved contralateral neural networks can assist in any observed recovery.Electrophysiological recordings from brainstem regions show antidromic activation of a small population of neurons in response to electrical stimulation caudal to the injury.These neurons are located in the Gigantocellular nucleus of reticular formation and vestibular nuclei,both regions directly related to motor functions.Together with histological features at the lesion site,such as more abundant and larger blood vessels and more abundant,longer and more homogeneously distributed axons,our results corroborate that rGO scaffolds create a permissive environment that allows the invasion of functional axonic processes from neurons located in brainstem nuclei with motor function in a rat model of complete thoracic transection.Additionally,behavioral tests evidence that these scaffolds play an important role in whole-body mechanical stabilization(postural control)proved by the absence of scoliosis,a higher trunk stability and a larger cervico-thoraco-lumbar movement range in rGO-implanted rats.展开更多
基金financially supported by the National Natural Science Foundation of China,No.81371366(to HFW)Characteristic Innovation Project of Colleges and Universities in Guangdong Province of China,No.2018KTSCX075(to HFW)+3 种基金the Key Project of Social Development of Dongguan of China,No.20185071521640(to HFW)College Students’ Science and Technology Innovation Training Project,China,Nos.201810571058,GDMU2018024,GDMU2018056,GDMU2018061(to HFW)College Students’ Innovative Experimental Project in Guangdong Medical University,China,No.ZZDS001(to HFW)College Students’ Science and Technology Innovation Cultivation Project in Guangdong of China,No.pdjh2019b0217(to HFW)
文摘Long non-coding RNAs(lncRNAs)are abundantly expressed in the central nervous system and exert a critical role in gene regulation via multiple biological processes.To uncover the functional significance and molecular mechanisms of lncRNAs in spinal cord injury(SCI),the expression signatures of lncRNAs were profiled using RNA sequencing(RNA-seq)technology in a Sprague-Dawley rat model of the 10th thoracic vertebra complete transection SCI.Results showed that 116 of 14,802 detected lncRNAs were differentially expressed,among which 16—including eight up-regulated(H19,Vof16,Hmox2-ps1,LOC100910973,Ybx1-ps3,Nnat,Gcgr,LOC680254)and eight down-regulated(Rmrp,Terc,Ngrn,Ppp2r2b,Cox6a2,Rpl37a-ps1,LOC360231,Rpph1)—demonstrated fold changes>2 in response to transection SCI.A subset of these RNA-seq results was validated by quantitative real-time PCR.The levels of 821 mRNAs were also significantly altered post-SCI;592 mRNAs were up-regulated and 229 mRNAs were down-regulated by more than 2-fold.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses showed that differentially expressed mRNAs were related to GO biological processes and molecular functions such as injury and inflammation response,wound repair,and apoptosis,and were significantly enriched in 15 KEGG pathways,including cell phagocytosis,tumor necrosis factor alpha pathway,and leukocyte migration.Our results reveal the expression profiles of lncRNAs and mRNAs in the rat spinal cord of a complete transection model,and these differentially expressed lncRNAs and mRNAs represent potential novel targets for SCI treatment.We suggest that lncRNAs may play an important role in the early immuno-inflammatory response after spinal cord injury.This study was approved by the Administration Committee of Experimental Animals,Guangdong Province,China.
文摘OBJECTIVE： To evaluate the effects of olfactory ensheathing cell transplantation on functional recovery of rats with complete spinal cord transection. DATA SOURCES： A computer-based online search of Medline （1989-2013）, Embase （1989- 2013）, Cochrane library （1989-2013）, Chinese Biomedical Literature Database （1989-2013）, China National Knowledge Infrastructure （1989-2013）, VIP （1989-2013）, Wanfang databases （1989-2013） and Chinese Clinical Trial Register was conducted to collect randomized controlled trial data regarding olfactory ensheathing cell transplantation for the treatment of complete spinal cord transection in rats. SELECTION CRITERIA： Randomized controlled trials investigating olfactory ensheathing cell transplantation and other transplantation methods for promoting neurological functional recov- ery of rats with complete spinal cord transection were included in the analysis. Meta analysis was conducted using RevMan 4.2.2 software. MAIN OUTCOME MEASURES： Basso, Beattie and Bresnahan scores of rats with complete spinal cord transection were evaluated in this study. RESULTS： Six randomized controlled trials with high quality methodology were included. Meta analysis showed that Basso, Beattie and Bresnahan scores were significantly higher in the olfacto- ry ensheathing cell transplantation group compared with the control group （WMD = 3.16, 95% （21 （1.68, 4.65）; P 〈 0.00001）. CONCLUSION： Experimental studies have shown that olfactory ensheathing cell transplantation can promote the functional recovery of motor nerves in rats with complete spinal cord transection.
文摘Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete injury.However,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental importance.The reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural regeneration.Thus,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies.First,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further investigation.Here,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.
基金supported by the National Key Research and Development Program of China,No.2017YFA0104304(to NG)the National Natural Science Foundation of China,Nos.81571213(to BW),81800583(to YYX),81601539(to DM)+2 种基金the Nanjing Medical Science and Technique Development Foundation of China,Nos.QRX17006(to BW),QRX17057(to DM)the Key Project Supported by Medical Science and Technology Development Foundation,Nanjing Department of Health and the Nanjing Medical Science and Innovation Platform of China,No.ZDX16005(to BW)Chongqing Yuzhong District Science and Technology Commission Project of China,No.20140112(to YYC).
文摘Collagen scaffolds possess a three-dimensional porous structure that provides sufficient space for cell growth and proliferation,the passage of nutrients and oxygen,and the discharge of metabolites.In this study,a porous collagen scaffold with axially-aligned luminal conduits was prepared.In vitro biocompatibility analysis of the collagen scaffold revealed that it enhances the activity of neural stem cells and promotes cell extension,without affecting cell differentiation.The collagen scaffold loaded with neural stem cells improved the hindlimb motor function in the rat model of T8 complete transection and promoted nerve regeneration.The collagen scaffold was completely degraded in vivo within 5 weeks of implantation,exhibiting good biodegradability.Rectal temperature,C-reactive protein expression and CD68 staining demonstrated that rats with spinal cord injury that underwent implantation of the collagen scaffold had no notable inflammatory reaction.These findings suggest that this novel collagen scaffold is a good carrier for neural stem cell transplantation,thereby enhancing spinal cord repair following injury.This study was approved by the Animal Ethics Committee of Nanjing Drum Tower Hospital(the Affiliated Hospital of Nanjing University Medical School),China(approval No.2019AE02005)on June 15,2019.
基金the Scientific and Technological Foundation of Hunan Public Health Bureau,No.B2006-034
文摘BACKGROUND:The establishment of a rat model of complete transected spinal cord injury lacks technological specifications.The current models lack concordance and reliability,and the death rate of the experimental animals is high.Therefore,there is a great need for a reliable model to apply clinical applications of therapy.OBJECTIVE:To construct a rat model of complete transected spinal cord injury characterized by stability,reproducibility,and a high animal survival rate.DESIGN:Completely randomized controlled study.SETTING:Department of Neurosurgery,Xiangya Hospital of Central South University.MATERIALS:Fifty-five healthy specific pathogen free grade adult female Sprague Dawley rats were provided by the Experimental Animal Department,Xiangya Medical College,Central South University.Olympus BX51 imaging collecting analytic system was provided by Olympus Company,Japan;and SEN-7203 Nihon-Kohden electrical stimulator by Nihon Kohden,Japan.METHODS:This study was performed at the Laboratory of Neurosurgery,Xiangya Hospital of Central South University from April to June 2006.Experimental grouping:55 rats were randomly divided into model group(n=40)and sham surgery group(n=15).In the model group,a self-made sliver hook was passed through the ventral side to support the spinal cord at the T12 segment and to shear it off.A complete transected spinal cord,2 mm in length,was resected.In the sham surgery group,the spinal cord was identically exposed.The dura mater of the spinal cord was cut open,but the spinal cord was not damaged.MAIN OUTCOME MEASURES:Histopathological changes after spinal cord injury at L2 segment were observed subsequent to hematoxylin and eosin staining under optical microscopy.Olympus BX51 imaging collecting analytic system was used to count spinal cord ventral horn neurons.Motor function of rat hindlimb was evaluated with the Basso,Beattie and Bresnahan(BBB)scale.Paraplegia was evaluated as 0 point,and complete normality as 21 points.Somatosensory-evoked potential was measured using Nihon-Kohden electric stimulator at 21 days post-operation.RESULTS:A total of 82%(33/40)rats survived longer than 30 days after modeling.Pathological changes of spinal cord tissue:degenerative and necrotic pathological changes appeared in the model group after surgery;for example,neuronal swelling,chromatinolysis,and karyopyknosis.The spinal cord in the sham surgery group displayed mild edema 24 hours after surgery,gradually recovering to normal levels.Quantification of spinal cord ventral horn neurons:the number of spinal cord ventral horn neurons in the model group was less than in the sham surgery group at 24 hours,as well as 7 and 21 days after surgery(P〈0.01);while,the number at 7 and 21 days after surgery decreased compared to 24 hours after surgery(P〈0.01).Motor function changes:Rats in the sham operation group moved lightly abnormally following anesthesia recovery and then moved normally 7 days after surgery.BBB scores in the model group were less than in the sham surgery group 21 days after surgery(P〈0.01).BBB scores of both lower extremities increased slightly 7 days after surgery(P〈0.01);however,voluntary motor function of both lower extremities was still not recovered 30 days after surgery.Changes of somatosensory-evoked potential:wave form of somatosensory-evoked potential was normal in the sham surgery group 21 days after surgery,but recovered wave form was not recorded in the model group.CONCLUSION:Results from spinal cord histopathology,cytology,motor function,and somatosensory-evoked potential suggested that the complete transected spinal cord injury model in this study was stable,reliable,and reproducible.Furthermore,the survival rate of experimental animals was high.
基金supported by the key Research Program of the Chinese Academy of Sciences (ZDRW-ZS-2016-2)the"Strategic Priority Research Program of the Chinese Academy of Sciences"(XDA01030000)
文摘Traumatic spinal cord injury (SCI) usually results in devastating neurologic deficits and disability. In the United States,approximately 12,500 new cases are reported each year, while an estimated 100,000–140,000 new cases occur every year in China (National Spinal Cord Injury Statistical Center, 2016).Spinal cord injuries are highly disabling and primarily affect young adults, and therefore create great psychological and financial burden on the affected individuals and their families.
基金funding from the European Union’s Horizon Europe research and Innovation Programme under grant agreement No.101098597(Piezo4Spine)supported by grant PID2020-113480RB-I00 funded by MCIN/AEI/10.13039/501100011033/supported by the Spanish State Funding Agency through project PID2022-139776NB-C66.
文摘Millions of patients and their caretakers live and deal with the devastating consequences of spinal cord injury(SCI)worldwide.Despite outstanding advances in the field to both understand and tackle these pathologies,a cure for SCI patients,with their peculiar characteristics,is still a mirage.One of the most promising therapeutic strategies to date for these patients involves the use of epidural electrical stimulation.In this context,electrically active materials such as graphene and its derivates become particularly interesting.Indeed,solid evidence of their capacity to closely interact with neural cells and networks is growing.Encouraged by previous findings in our laboratory on the exploration of 3D porous reduced graphene oxide(rGO)scaffolds in chronic cervical hemisected rats(C6),herein we report their neuro-reparative properties when chronically implanted in complete transected rats(T9-T10),in which no preserved contralateral neural networks can assist in any observed recovery.Electrophysiological recordings from brainstem regions show antidromic activation of a small population of neurons in response to electrical stimulation caudal to the injury.These neurons are located in the Gigantocellular nucleus of reticular formation and vestibular nuclei,both regions directly related to motor functions.Together with histological features at the lesion site,such as more abundant and larger blood vessels and more abundant,longer and more homogeneously distributed axons,our results corroborate that rGO scaffolds create a permissive environment that allows the invasion of functional axonic processes from neurons located in brainstem nuclei with motor function in a rat model of complete thoracic transection.Additionally,behavioral tests evidence that these scaffolds play an important role in whole-body mechanical stabilization(postural control)proved by the absence of scoliosis,a higher trunk stability and a larger cervico-thoraco-lumbar movement range in rGO-implanted rats.
