Use of a combination strategy to improve neuroprotection and neuroregeneration in a rat model of acute spinal cord injury
|
摘要
Spinal cord injury is a very common pathological event that has devastating functional consequences in patients. In recent years, several research groups are trying to find an effective therapy that could be applied in clinical practice. In this study, we analyzed the combination of different strategies as a potential therapy for spinal cord injury. Immunization with neural derived peptides(INDP), inhibition of glial scar formation(dipyridyl: DPY), as well as the use of biocompatible matrix(fibrin glue: FG) impregnated with bone marrow mesenchymal stem cells(MSCs) were combined and then its beneficial effects were evaluated in the induction of neuroprotection and neuroregeneration after acute SCI. Sprague-Dawley female rats were subjected to a moderate spinal cord injury and then randomly allocated into five groups: 1) phosphate buffered saline; 2) DPY; 3) INDP + DPY; 4) DPY+ FG; 5) INDP + DPY + FG + MSCs. In all rats, intervention was performed 72 hours after spinal cord injury. Locomotor and sensibility recovery was assessed in all rats. At 60 days after treatment, histological examinations of the spinal cord(hematoxylin-eosin and Bielschowsky staining) were performed. Our results showed that the combination therapy(DPY+ INDP + FG+ MSCs) was the best strategy to promote motor and sensibility recovery. In addition, significant increases in tissue preservation and axonal density were observed in the combination therapy group. Findings from this study suggest that the combination theapy(DPY+ INDP + FG + MSCs) exhibits potential effects on the protection and regeneration of neural tissue after acute spinal cord injury. All procedures were approved by the Animal Bioethics and Welfare Committee(approval No. 178544; CSNBTBIBAJ 090812960)on August 15, 2016.
Spinal cord injury is a very common pathological event that has devastating functional consequences in patients. In recent years, several research groups are trying to find an effective therapy that could be applied in clinical practice. In this study, we analyzed the combination of different strategies as a potential therapy for spinal cord injury. Immunization with neural derived peptides(INDP), inhibition of glial scar formation(dipyridyl: DPY), as well as the use of biocompatible matrix(fibrin glue: FG) impregnated with bone marrow mesenchymal stem cells(MSCs) were combined and then its beneficial effects were evaluated in the induction of neuroprotection and neuroregeneration after acute SCI. Sprague-Dawley female rats were subjected to a moderate spinal cord injury and then randomly allocated into five groups: 1) phosphate buffered saline; 2) DPY; 3) INDP + DPY; 4) DPY+ FG; 5) INDP + DPY + FG + MSCs. In all rats, intervention was performed 72 hours after spinal cord injury. Locomotor and sensibility recovery was assessed in all rats. At 60 days after treatment, histological examinations of the spinal cord(hematoxylin-eosin and Bielschowsky staining) were performed. Our results showed that the combination therapy(DPY+ INDP + FG+ MSCs) was the best strategy to promote motor and sensibility recovery. In addition, significant increases in tissue preservation and axonal density were observed in the combination therapy group. Findings from this study suggest that the combination theapy(DPY+ INDP + FG + MSCs) exhibits potential effects on the protection and regeneration of neural tissue after acute spinal cord injury. All procedures were approved by the Animal Bioethics and Welfare Committee(approval No. 178544; CSNBTBIBAJ 090812960)on August 15, 2016.
Spinal cord injury is a very common pathological event that has devastating functional consequences in patients. In recent years, several research groups are trying to find an effective therapy that could be applied in clinical practice. In this study, we analyzed the combination of different strategies as a potential therapy for spinal cord injury. Immunization with neural derived peptides(INDP), inhibition of glial scar formation(dipyridyl: DPY), as well as the use of biocompatible matrix(fibrin glue: FG) impregnated with bone marrow mesenchymal stem cells(MSCs) were combined and then its beneficial effects were evaluated in the induction of neuroprotection and neuroregeneration after acute SCI. Sprague-Dawley female rats were subjected to a moderate spinal cord injury and then randomly allocated into five groups: 1) phosphate buffered saline; 2) DPY; 3) INDP + DPY; 4) DPY+ FG; 5) INDP + DPY + FG + MSCs. In all rats, intervention was performed 72 hours after spinal cord injury. Locomotor and sensibility recovery was assessed in all rats. At 60 days after treatment, histological examinations of the spinal cord(hematoxylin-eosin and Bielschowsky staining) were performed. Our results showed that the combination therapy(DPY+ INDP + FG+ MSCs) was the best strategy to promote motor and sensibility recovery. In addition, significant increases in tissue preservation and axonal density were observed in the combination therapy group. Findings from this study suggest that the combination theapy(DPY+ INDP + FG + MSCs) exhibits potential effects on the protection and regeneration of neural tissue after acute spinal cord injury. All procedures were approved by the Animal Bioethics and Welfare Committee(approval No. 178544; CSNBTBIBAJ 090812960)on August 15, 2016.
引文
Barbizan R,Castro MV,Barraviera B,Ferreira RS Jr,Oliveira AL(2014)Influence of delivery method on neuroprotection by bone marrow mononuclear cell therapy following ventral root reimplantation with fibrin sealant.PLoS One 9:e105712.
Barbizan R,Castro MV,Rodrigues AC,Barraviera B,Ferreira RS,Oliveira AL(2013)Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom.PLoS One 8:e63260.
Barnabé-Heider F,Frisén J(2008)Stem cells for spinal cord repair.Cell Stem Cell 3:16-24.
Basso DM.,Beattie MS,Bresnahan JC(1995)A sensitive and reliable locomotor rating scale for open field testing in rats.J Neurotrauma12:1-21.
Beck KD,Nguyen HX,Galvan MD,Salazar DL,Woodruff TM,Anderson AJ(2010)Quantitative analysis of cellular inflammation after traumatic spinal cord injury:Evidence for a multiphasic inflammatory response in the acute to chronic environment.Brain133:433-447.
Berrocal YA,Almeida VW,Puentes R,Knott EP,Hechtman JF,Garland M,Pearse DD(2014)Loss of central inhibition:Implications for behavioral hypersensitivity after contusive cpinal cord injury in rats.Pain Res Treat 2014:178278
Buzoianu-Anguiano V,Orozco-Suárez S,García-Vences E,Caballero-Chacón S,Guizar-Sahagún G,Chavez-Sanchez L,Grijalva I(2015)The morphofunctional effect of the transplantation of bone marrow stromal cells and predegenerated peripheral nerve in chronic paraplegic rat model via spinal cord transection.Neural Plast 2015:389520.
Cassell OC,Morrison WA,Messina A,Penington AJ,Thompson EW,Stevens GW Kinght KR(2001)The influence of extracellular matrix on the generation of vascularized,engineered,transplantable tissue.Ann N Y Acad Sci 944:429-442.
Cheng H,Almstr?m S,Olson L,Cheng H(1995)Fibrin glue used as an adhesive agent in CNS tissues.J Neural Transplant Plast 5:233-243.
Chiba Y,Kuroda S,Maruichi K,Osanai T,Hokari M,Yano S,Shichinohe H,Hida K,Iwasaki Y(2009)Transplanted bone marrow stromal cells promote axonal regeneration and improve motor function in a rat spinal cord injury model.Neurosurgery 64:991-999.
Colburn RW,Rickman AJ,DeLeo JA(1999)The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior.Exp Neurol 157:289-304.
Cruz Y,García E,Gálvez JV,Arias-Santiago SV,Carvajal HG,Silva-García R,Ibarra A(2018)Release of interleukin-10 and neurotrophic factors in the choroid plexus:possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia.Neural Regen Res 13:1743-1752.
Cruz Y,Lorea J,Mestre H,Kim-Lee JH,Herrera J,Mellado R,Ibarra A(2015)Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats.PLoS One10:e0121854.
Del Rayo Garrido M,Silva-García R,García E,Marti?ón S,Morales M,Mestre H,Flores-Domínguez C,Flores A,Ibarra A(2013)Therapeutic window for combination therapy of A91 peptide and glutathione allows delayed treatment after spinal cord injury.Basic Clin Pharmacol Toxicol 112:314-318.
Dietrich WD,Chatzipanteli K,Vitarbo E,Wada K,Kinoshita K(2004)The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma.Acta Neurochir Suppl89:69-74.
Donnelly DJ,Popovich PG(2008)Inflammation and its role in neuroprotection,axonal regeneration and functional recovery after spinal cord injury.Exp Neurol 209:378-388.
Fitch MT,Silver J(2008)CNS injury,glial scars,and inflammation:Inhibitory extracellular matrices and regeneration failure.Exp Neurol 209:294-301.
Franz S,Ciatipis M,Pfeifer K,Kierdorf B,Sandner B,Bogdahn U,Blesh A,Winner B(2014)Thoracic rat spinal cord contusion injury induces remote spinal gliogenesis but not neurogenesis or gliogenesis in the brain.PLoS One 9:e102896.
Gallo V,Deneen B(2014)Glial development:The crossroads of regeneration and repair in the CNS.Neuron 83:283-308.
García E,Silva-García R,Flores-Romero A,Blancas-Espinoza L,Rodríguez-Barrera R,Ibarra A(2018)The severity of spinal cord injury determines the inflammatory gene expression pattern after immunization with neural-derived peptides.J Mol Neurosci65:190-195.
Garcia E,Silva-Garcia R,Mestre H,Flores N,Martinon S,Calderon-Aranda ES,Ibarra A(2012)Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury.JNeurosci Res 90:656-663.
Garman R(2011)Histology of the central nervous system.Toxicol Pathol 39:22-35.
Gu W,Zhang F,Xue Q,Ma Z,Lu P,Yu B(2010)Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord.Neuropathology30:205-217.
Hu R,Zhou J,Luo C,Lin J,Wang X,Li X,Feng H(2010)Glial scar and neuroregeneration:histological,functional,and magnetic resonance imaging analysis in chronic spinal cord injury.J Neurosurg Spine 13:169-180.
Ibarra A,Garcia E,Flores N,Marti?ón S,Reyes R,Campos MG,Mestre H(2010)Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury.Neurosci Lett 476:62-65.
Ikeda H,Wu GY,Wu CH(1992)Evidence that an iron chelator regulates collagen synthesis by decreasing the stability of procollagen mRNA.Hepatology 15:282-287.
Kan EM,Ling EA,Lu J(2010)Stem cell therapy for spinal cord injury.Curr Med Chem 17:4492-4510.
Kasahara K,Nakagawa T,Kubota T(2006)Neuronal loss and expression of neurotrophic factors in a model of rat chronic compressive spinal cord injury.Spine 31:2059-2066.
Klapka N,Hermanns S,Straten G,Masanneck C,Duis S,Hamers FP,Müller HW(2005)Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons,rescue of primary motoneurons in somatosensory cortex and significant functional recovery.Eur J Neurosci 22:3047-3058.
Krabbe C,Zimmer J,Meyer M(2005)Neural transdifferentiation of mesenchymal stem cells--a critical review.APMIS 113(11-12):831-844.
Litchfield S,Nagy Z(2001)New temperature modification makes the Bielschowsky silver stain reproducible.Acta Neuropathol 101:17-21.
Liu J,Chen Q,Zhang Z,Zheng Y,Sun X,Cao X,Jiang P(2013)Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury.Cells Tissues Organs 198:35-46.
Liu XZ,Xu XM,Hu R,Du C,Zhang SX,McDonald JW,Choi DW(1997)Neuronal and glial apoptosis after traumatic spinal cord injury.J Neurosci 17:5395-5406.
Lu P,Jones LL,Tuszynski MH(2005)BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury.Exp Neurol 191:344-360.
Marti?ón S,García E,Gutierrez-Ospina G,Mestre H,Ibarra A(2012)Development of protective autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury.PLoS One 7:e32027.
Marti?ón S,García-Vences E,Toscano-Tejeida D,Flores-Romero A,Rodriguez-Barrera R,Ferrusquia,Ibarra A(2016)Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.BMC Neurosci 17:42.
Menovsky T,Beek JF(2001)Laser,fibrin glue,or suture repair of peripheral nerves:a comparative functional,histological,and morphometric study in the rat sciatic nerve.J Neurosurg 95:694-699.
Nakajima H,Uchida K,Guerrero AR,Watanabe S,Sugita D,Takeura N,Baba H(2012)Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury.J Neurotrauma 29:1614-1625.
Neuhuber B,Timothy Himes B,Shumsky JS,Gallo G,Fischer I(2005)Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations.Brain Res 1035:73-85.
Niclou SP,Ehlert EM,Verhaagen J(2006)Chemorepellent axon guidance molecules in spinal cord injury.J Neurotrauma 23(3-4):409-421.
Ohta M,Suzuki Y,Noda T,Ejiri Y,Dezawa M,Kataoka K,Ide C(2004)Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation.Exp Neurol 187:266-278.
Popovich PG(2014)Neuroimmunology of traumatic spinal cord injury:a brief history and overview.Exp Neurol 258:1-4.
Quertainmont R,Cantinieaux D,Botman O,Sid S,Schoenen J,Franzen R(2012)Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions.PLoS One 7:e39500
Rodríguez-Barrera R,Fernández-Presas AM,García E,Flores-Romero A,Marti?ón S,González-Puertos VY,Ibarra A(2013)Immunization with a neural-derived peptide protects the spinal cord from apoptosis after traumatic injury.Biomed Res Int 2013:827517.
Rodríguez-Barrera R,Flores-Romero A,Fernández-Presas AM,García-Vences E,Silva-García R,Konigsberg M,Ibarra A(2017)Immunization with neural derived peptides plus scar removal induces a permissive microenvironment,and improves locomotor recovery after chronic spinal cord injury.BMC Neurosci 18:7.
Schiwy N,Brazda N,Müller HW(2009)Enhanced regenerative axon growth of multiple fibre populations in traumatic spinal cord injury following scar-suppressing treatment.Eur J Neurosci 30:1544-1553.
Silver J,Miller JH(2004)Regeneration beyond the glial scar.Nat Rev Neurosci 5:146-156.
Sundberg LM,Herrera JJ,Narayana P(2010)In vivo longitudinal MRI and behavioral studies in experimental spinal cord injury.JNeurotrauma 27:1753-1767.
Trivedi A,Olivas AD,Noble-Haeusslein LJ(2006)Inflammation and spinal cord injury:Infiltrating leukocytes as determinants of injury and repair processes.Clin Neurosci Res 6:283-292.
Vaquero J,Zurita M(2009)Bone marrow stromal cells for spinal cord repair:a challenge for contemporary neurobiology.Histol Histopathol 24:107-116.
Vogel C,Rukwied R,Stockinger L,Schley M,Schmelz M,Schleinzer W,Konrad C(2017)Functional characterization of at-level hypersensitivity in patients with spinal cord injury.J Pain 18:66-78.
Xiao Z,Tang F,Tang J,Yang H,Zhao Y,Chen B,Dai J(2016)Oneyear clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients.Sci China Life Sci 59:647-655.
Ziv Y,Finkelstein A,Geffen Y,Kipnis J,Smirnov I,Shpilman S,Yoles E(2007)A novel immune-based therapy for stroke induces neuroprotection and supports neurogenesis.Stroke 38(2 Suppl):774-782.
Barbizan R,Castro MV,Rodrigues AC,Barraviera B,Ferreira RS,Oliveira AL(2013)Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom.PLoS One 8:e63260.
Barnabé-Heider F,Frisén J(2008)Stem cells for spinal cord repair.Cell Stem Cell 3:16-24.
Basso DM.,Beattie MS,Bresnahan JC(1995)A sensitive and reliable locomotor rating scale for open field testing in rats.J Neurotrauma12:1-21.
Beck KD,Nguyen HX,Galvan MD,Salazar DL,Woodruff TM,Anderson AJ(2010)Quantitative analysis of cellular inflammation after traumatic spinal cord injury:Evidence for a multiphasic inflammatory response in the acute to chronic environment.Brain133:433-447.
Berrocal YA,Almeida VW,Puentes R,Knott EP,Hechtman JF,Garland M,Pearse DD(2014)Loss of central inhibition:Implications for behavioral hypersensitivity after contusive cpinal cord injury in rats.Pain Res Treat 2014:178278
Buzoianu-Anguiano V,Orozco-Suárez S,García-Vences E,Caballero-Chacón S,Guizar-Sahagún G,Chavez-Sanchez L,Grijalva I(2015)The morphofunctional effect of the transplantation of bone marrow stromal cells and predegenerated peripheral nerve in chronic paraplegic rat model via spinal cord transection.Neural Plast 2015:389520.
Cassell OC,Morrison WA,Messina A,Penington AJ,Thompson EW,Stevens GW Kinght KR(2001)The influence of extracellular matrix on the generation of vascularized,engineered,transplantable tissue.Ann N Y Acad Sci 944:429-442.
Cheng H,Almstr?m S,Olson L,Cheng H(1995)Fibrin glue used as an adhesive agent in CNS tissues.J Neural Transplant Plast 5:233-243.
Chiba Y,Kuroda S,Maruichi K,Osanai T,Hokari M,Yano S,Shichinohe H,Hida K,Iwasaki Y(2009)Transplanted bone marrow stromal cells promote axonal regeneration and improve motor function in a rat spinal cord injury model.Neurosurgery 64:991-999.
Colburn RW,Rickman AJ,DeLeo JA(1999)The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior.Exp Neurol 157:289-304.
Cruz Y,García E,Gálvez JV,Arias-Santiago SV,Carvajal HG,Silva-García R,Ibarra A(2018)Release of interleukin-10 and neurotrophic factors in the choroid plexus:possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia.Neural Regen Res 13:1743-1752.
Cruz Y,Lorea J,Mestre H,Kim-Lee JH,Herrera J,Mellado R,Ibarra A(2015)Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats.PLoS One10:e0121854.
Del Rayo Garrido M,Silva-García R,García E,Marti?ón S,Morales M,Mestre H,Flores-Domínguez C,Flores A,Ibarra A(2013)Therapeutic window for combination therapy of A91 peptide and glutathione allows delayed treatment after spinal cord injury.Basic Clin Pharmacol Toxicol 112:314-318.
Dietrich WD,Chatzipanteli K,Vitarbo E,Wada K,Kinoshita K(2004)The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma.Acta Neurochir Suppl89:69-74.
Donnelly DJ,Popovich PG(2008)Inflammation and its role in neuroprotection,axonal regeneration and functional recovery after spinal cord injury.Exp Neurol 209:378-388.
Fitch MT,Silver J(2008)CNS injury,glial scars,and inflammation:Inhibitory extracellular matrices and regeneration failure.Exp Neurol 209:294-301.
Franz S,Ciatipis M,Pfeifer K,Kierdorf B,Sandner B,Bogdahn U,Blesh A,Winner B(2014)Thoracic rat spinal cord contusion injury induces remote spinal gliogenesis but not neurogenesis or gliogenesis in the brain.PLoS One 9:e102896.
Gallo V,Deneen B(2014)Glial development:The crossroads of regeneration and repair in the CNS.Neuron 83:283-308.
García E,Silva-García R,Flores-Romero A,Blancas-Espinoza L,Rodríguez-Barrera R,Ibarra A(2018)The severity of spinal cord injury determines the inflammatory gene expression pattern after immunization with neural-derived peptides.J Mol Neurosci65:190-195.
Garcia E,Silva-Garcia R,Mestre H,Flores N,Martinon S,Calderon-Aranda ES,Ibarra A(2012)Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury.JNeurosci Res 90:656-663.
Garman R(2011)Histology of the central nervous system.Toxicol Pathol 39:22-35.
Gu W,Zhang F,Xue Q,Ma Z,Lu P,Yu B(2010)Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord.Neuropathology30:205-217.
Hu R,Zhou J,Luo C,Lin J,Wang X,Li X,Feng H(2010)Glial scar and neuroregeneration:histological,functional,and magnetic resonance imaging analysis in chronic spinal cord injury.J Neurosurg Spine 13:169-180.
Ibarra A,Garcia E,Flores N,Marti?ón S,Reyes R,Campos MG,Mestre H(2010)Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury.Neurosci Lett 476:62-65.
Ikeda H,Wu GY,Wu CH(1992)Evidence that an iron chelator regulates collagen synthesis by decreasing the stability of procollagen mRNA.Hepatology 15:282-287.
Kan EM,Ling EA,Lu J(2010)Stem cell therapy for spinal cord injury.Curr Med Chem 17:4492-4510.
Kasahara K,Nakagawa T,Kubota T(2006)Neuronal loss and expression of neurotrophic factors in a model of rat chronic compressive spinal cord injury.Spine 31:2059-2066.
Klapka N,Hermanns S,Straten G,Masanneck C,Duis S,Hamers FP,Müller HW(2005)Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons,rescue of primary motoneurons in somatosensory cortex and significant functional recovery.Eur J Neurosci 22:3047-3058.
Krabbe C,Zimmer J,Meyer M(2005)Neural transdifferentiation of mesenchymal stem cells--a critical review.APMIS 113(11-12):831-844.
Litchfield S,Nagy Z(2001)New temperature modification makes the Bielschowsky silver stain reproducible.Acta Neuropathol 101:17-21.
Liu J,Chen Q,Zhang Z,Zheng Y,Sun X,Cao X,Jiang P(2013)Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury.Cells Tissues Organs 198:35-46.
Liu XZ,Xu XM,Hu R,Du C,Zhang SX,McDonald JW,Choi DW(1997)Neuronal and glial apoptosis after traumatic spinal cord injury.J Neurosci 17:5395-5406.
Lu P,Jones LL,Tuszynski MH(2005)BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury.Exp Neurol 191:344-360.
Marti?ón S,García E,Gutierrez-Ospina G,Mestre H,Ibarra A(2012)Development of protective autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury.PLoS One 7:e32027.
Marti?ón S,García-Vences E,Toscano-Tejeida D,Flores-Romero A,Rodriguez-Barrera R,Ferrusquia,Ibarra A(2016)Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury.BMC Neurosci 17:42.
Menovsky T,Beek JF(2001)Laser,fibrin glue,or suture repair of peripheral nerves:a comparative functional,histological,and morphometric study in the rat sciatic nerve.J Neurosurg 95:694-699.
Nakajima H,Uchida K,Guerrero AR,Watanabe S,Sugita D,Takeura N,Baba H(2012)Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury.J Neurotrauma 29:1614-1625.
Neuhuber B,Timothy Himes B,Shumsky JS,Gallo G,Fischer I(2005)Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations.Brain Res 1035:73-85.
Niclou SP,Ehlert EM,Verhaagen J(2006)Chemorepellent axon guidance molecules in spinal cord injury.J Neurotrauma 23(3-4):409-421.
Ohta M,Suzuki Y,Noda T,Ejiri Y,Dezawa M,Kataoka K,Ide C(2004)Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation.Exp Neurol 187:266-278.
Popovich PG(2014)Neuroimmunology of traumatic spinal cord injury:a brief history and overview.Exp Neurol 258:1-4.
Quertainmont R,Cantinieaux D,Botman O,Sid S,Schoenen J,Franzen R(2012)Mesenchymal stem cell graft improves recovery after spinal cord injury in adult rats through neurotrophic and pro-angiogenic actions.PLoS One 7:e39500
Rodríguez-Barrera R,Fernández-Presas AM,García E,Flores-Romero A,Marti?ón S,González-Puertos VY,Ibarra A(2013)Immunization with a neural-derived peptide protects the spinal cord from apoptosis after traumatic injury.Biomed Res Int 2013:827517.
Rodríguez-Barrera R,Flores-Romero A,Fernández-Presas AM,García-Vences E,Silva-García R,Konigsberg M,Ibarra A(2017)Immunization with neural derived peptides plus scar removal induces a permissive microenvironment,and improves locomotor recovery after chronic spinal cord injury.BMC Neurosci 18:7.
Schiwy N,Brazda N,Müller HW(2009)Enhanced regenerative axon growth of multiple fibre populations in traumatic spinal cord injury following scar-suppressing treatment.Eur J Neurosci 30:1544-1553.
Silver J,Miller JH(2004)Regeneration beyond the glial scar.Nat Rev Neurosci 5:146-156.
Sundberg LM,Herrera JJ,Narayana P(2010)In vivo longitudinal MRI and behavioral studies in experimental spinal cord injury.JNeurotrauma 27:1753-1767.
Trivedi A,Olivas AD,Noble-Haeusslein LJ(2006)Inflammation and spinal cord injury:Infiltrating leukocytes as determinants of injury and repair processes.Clin Neurosci Res 6:283-292.
Vaquero J,Zurita M(2009)Bone marrow stromal cells for spinal cord repair:a challenge for contemporary neurobiology.Histol Histopathol 24:107-116.
Vogel C,Rukwied R,Stockinger L,Schley M,Schmelz M,Schleinzer W,Konrad C(2017)Functional characterization of at-level hypersensitivity in patients with spinal cord injury.J Pain 18:66-78.
Xiao Z,Tang F,Tang J,Yang H,Zhao Y,Chen B,Dai J(2016)Oneyear clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients.Sci China Life Sci 59:647-655.
Ziv Y,Finkelstein A,Geffen Y,Kipnis J,Smirnov I,Shpilman S,Yoles E(2007)A novel immune-based therapy for stroke induces neuroprotection and supports neurogenesis.Stroke 38(2 Suppl):774-782.