Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration...Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.展开更多
As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment op...As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment option. At 5 days after T8 spinal cord crush injury, rats were injected with bone marrow mesenchymal stem cell suspension or chondroitinase ABC 1 mm from the edge of spinal cord damage zone. Chondroitinase ABC was first injected, and bone marrow mesenchymal stem cell suspension was injected on the next day in the combination group. At 14 days, the mean Basso, Beattie and Bresnahan score of the rats in the combination group was higher than other groups. Hematoxylin-eosin staining showed that the necrotic area was significantly reduced in the combination group compared with other groups. Glial fibrillary acidic protein-chondroitin sulfate proteoglycan double staining showed that the damage zone of astrocytic scars was significantly reduced without the cavity in the combination group. Glial fibrillary acidic protein/growth associated protein-43 double immunostaining revealed that positive fibers traversed the damage zone in the combination group. These results suggest that the combination of chondroitinase ABC and bone marrow mesenchymal stem cell transplantation contributes to the repair of spinal cord injury.展开更多
Sciatic nerves from allogeneic Sprague-Dawley rats were pretreated with chondroitinase ABC and were used to bridge damaged sciatic nerves in Wistar rats. Chondroitin sulfate proteoglycans were removed from the chemica...Sciatic nerves from allogeneic Sprague-Dawley rats were pretreated with chondroitinase ABC and were used to bridge damaged sciatic nerves in Wistar rats. Chondroitin sulfate proteoglycans were removed from the chemically extracted acellular nerves. At 3 months after grafting, the footplate pinch test result was positive in the Wistar rats. Autotorny scores decreased, and increased muscular contraction tension appeared when triceps surae muscles were stimulated. In addition, the recovery rate of wet triceps surae muscle weight increased, and the distal segment of the chondroitinase ABC-treated graft exhibited Schwann cells next to the nerve fibers. These results suggested that chondroitinase ABC pretreatment enhanced repair of long nerve defects via acellular nerve grafting.展开更多
Chondroitin sulfate proteoglycans （CSPGs） which are produced by mature oligodendrocytes and reactive astrocytes can be upregulated after spinal cord injury and contribute to regenerative failure. Chondroitinase ABC ...Chondroitin sulfate proteoglycans （CSPGs） which are produced by mature oligodendrocytes and reactive astrocytes can be upregulated after spinal cord injury and contribute to regenerative failure. Chondroitinase ABC （ChABC） digests glycosaminoglycan chains on CSPGs and can thereby overcome CSPG-mediated inhibition. However, many current studies have used an incomplete spinal cord injury model, and examined results after 8-12 weeks of ChABC treatment. In this study, a complete rat spinal cord transection injury model was used to study the long-term effects of ChABC treatment by subarachnoid catheter. Pathology of spinal cord regeneration was compared with control 24 weeks following ChABC treatment using immunohistochemistry and axon tracing techniques. At 24 weeks after injury, neurofilament 200 expression was significantly greater in the ChABC treatment group compared with the transection group. In the ChABC treatment group, axonal growth was demonstrated by a large number of biotinylated dextran amine positive axons caudal to, or past, the epicenter of injury. Biotinylated dextran amine-labeled fibers were found in the proximal end of the spinal cord in the transection alone group. These results confirm that ChABC can promote axon growth, neural regeneration, and repair after spinal cord injury in rats long after the initial injury.展开更多
基金supported in part by NIH R01 NS100531,R01 NS103481NIH R21NS130241(to LD)+3 种基金Merit Review Award I01 BX002356,I01 BX003705 from the U.S.Department of Veterans AffairsIndiana Spinal Cord and Brain Injury Research Foundation(No.19919)Mari Hulman George Endowment Funds(to XMX)Indiana Spinal Cord&Brain Injury Research Fund from ISDH(to NKL and LD)。
文摘Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.
文摘As chondroitinase ABC can improve the hostile microenvironment and cell transplantation is proven to be effective after spinal cord injury, we hypothesized that their combination would be a more effective treatment option. At 5 days after T8 spinal cord crush injury, rats were injected with bone marrow mesenchymal stem cell suspension or chondroitinase ABC 1 mm from the edge of spinal cord damage zone. Chondroitinase ABC was first injected, and bone marrow mesenchymal stem cell suspension was injected on the next day in the combination group. At 14 days, the mean Basso, Beattie and Bresnahan score of the rats in the combination group was higher than other groups. Hematoxylin-eosin staining showed that the necrotic area was significantly reduced in the combination group compared with other groups. Glial fibrillary acidic protein-chondroitin sulfate proteoglycan double staining showed that the damage zone of astrocytic scars was significantly reduced without the cavity in the combination group. Glial fibrillary acidic protein/growth associated protein-43 double immunostaining revealed that positive fibers traversed the damage zone in the combination group. These results suggest that the combination of chondroitinase ABC and bone marrow mesenchymal stem cell transplantation contributes to the repair of spinal cord injury.
基金funded by the Liaoning Scientific Research Foundation of Doctor, No. 20101134the Beijing Natural Science Foundation (The oriented micro-structure, double-aligned nerve-derived extracellular matrix scaffolds promote peripheral nerve long defects regeneration)
文摘Sciatic nerves from allogeneic Sprague-Dawley rats were pretreated with chondroitinase ABC and were used to bridge damaged sciatic nerves in Wistar rats. Chondroitin sulfate proteoglycans were removed from the chemically extracted acellular nerves. At 3 months after grafting, the footplate pinch test result was positive in the Wistar rats. Autotorny scores decreased, and increased muscular contraction tension appeared when triceps surae muscles were stimulated. In addition, the recovery rate of wet triceps surae muscle weight increased, and the distal segment of the chondroitinase ABC-treated graft exhibited Schwann cells next to the nerve fibers. These results suggested that chondroitinase ABC pretreatment enhanced repair of long nerve defects via acellular nerve grafting.
基金the National Natural Science Foundation of China,No.30471759
文摘Chondroitin sulfate proteoglycans （CSPGs） which are produced by mature oligodendrocytes and reactive astrocytes can be upregulated after spinal cord injury and contribute to regenerative failure. Chondroitinase ABC （ChABC） digests glycosaminoglycan chains on CSPGs and can thereby overcome CSPG-mediated inhibition. However, many current studies have used an incomplete spinal cord injury model, and examined results after 8-12 weeks of ChABC treatment. In this study, a complete rat spinal cord transection injury model was used to study the long-term effects of ChABC treatment by subarachnoid catheter. Pathology of spinal cord regeneration was compared with control 24 weeks following ChABC treatment using immunohistochemistry and axon tracing techniques. At 24 weeks after injury, neurofilament 200 expression was significantly greater in the ChABC treatment group compared with the transection group. In the ChABC treatment group, axonal growth was demonstrated by a large number of biotinylated dextran amine positive axons caudal to, or past, the epicenter of injury. Biotinylated dextran amine-labeled fibers were found in the proximal end of the spinal cord in the transection alone group. These results confirm that ChABC can promote axon growth, neural regeneration, and repair after spinal cord injury in rats long after the initial injury.
