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2.
Front Immunol ; 10: 2558, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736973

RESUMO

A previously unreported population of foam cells (foamy macrophages) accumulates in the invasive fibrotic meninges during gap regeneration of transected adult Axolotl spinal cord (salamander Ambystoma mexicanum) and may act beneficially. Multinucleated giant cells (MNGCs) also occurred in the fibrotic meninges. Actin-label localization and transmission electron microscopy showed characteristic foam cell and MNGC podosome and ruffled border-containing sealing ring structures involved in substratum attachment, with characteristic intermediate filament accumulations surrounding nuclei. These cells co-localized with regenerating cord ependymal cell (ependymoglial) outgrowth. Phase contrast-bright droplets labeled with Oil Red O, DiI, and DyRect polar lipid live cell label showed accumulated foamy macrophages to be heavily lipid-laden, while reactive ependymoglia contained smaller lipid droplets. Both cell types contained both neutral and polar lipids in lipid droplets. Foamy macrophages and ependymoglia expressed the lipid scavenger receptor CD36 (fatty acid translocase) and the co-transporter toll-like receptor-4 (TLR4). Competitive inhibitor treatment using the modified fatty acid Sulfo-N-succinimidyl Oleate verified the role of the lipid scavenger receptor CD36 in lipid uptake studies in vitro. Fluoromyelin staining showed both cell types took up myelin fragments in situ during the regeneration process. Foam cells took up DiI-Ox-LDL and DiI-myelin fragments in vitro while ependymoglia took up only DiI-myelin in vitro. Both cell types expressed the cysteine proteinase cathepsin K, with foam cells sequestering cathepsin K within the sealing ring adjacent to the culture substratum. The two cell types act as sinks for Ox-LDL and myelin fragments within the lesion site, with foamy macrophages showing more Ox-LDL uptake activity. Cathepsin K activity and cellular localization suggested that foamy macrophages digest ECM within reactive meninges, while ependymal cells act from within the spinal cord tissue during outgrowth into the lesion site, acting in complementary fashion. Small MNGCs also expressed lipid transporters and showed cathepsin K activity. Comparison of 3H-glucosamine uptake in ependymal cells and foam cells showed that only ependymal cells produce glycosaminoglycan and proteoglycan-containing ECM, while the cathepsin studies showed both cell types remove ECM. Interaction of foam cells and ependymoglia in vitro supported the dispersion of ependymal outgrowth associated with tissue reconstruction in Axolotl spinal cord regeneration.


Assuntos
Ambystoma mexicanum/imunologia , Epêndima/citologia , Epêndima/imunologia , Células Espumosas/imunologia , Meninges/citologia , Meninges/imunologia , Regeneração da Medula Espinal/imunologia , Ambystoma mexicanum/metabolismo , Animais , Catepsina K/imunologia , Feminino , Masculino , Bainha de Mielina/metabolismo , Medula Espinal/imunologia
3.
Curr Pharm Des ; 22(6): 728-37, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26635269

RESUMO

In the injured adult mammalian central nervous system (CNS), the failure of axonal regeneration is thought to be attributed, at least in part, to various myelin-associated inhibitors (MAIs), such as Nogo, myelinassociated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp) around the damaged site. Interestingly, these three structurally different inhibitors share two common receptors, Nogo-66 receptor (NgR) and paired immunoglobulin-like receptor B (PirB), and transduce the inhibitory signal into neurons via their complex combinant and co-receptors, such as p75 neurotrophin receptor (p75NTR), Nogo receptor-interacting protein 1 (LINGO-1), and TROY. Accordingly, targeting of the whole myelin or just portions by immunization has been proved to be neuroprotective and is able to promote regeneration in the injured spinal cords. In the past few years, vaccine approaches were initially achieved and could induce the production of antibodies against inhibitors in myelin to block the inhibitory effects and promote functional recovery in spinal cord injury (SCI) models by immunizing with MAIs, such as purified myelin, spinal cord homogenates, or their receptors with the concept of protective autoimmunity formulated. However, for safety consideration, further work is necessary before the immunotherapy strategies can be adopted to treat human injured spinal cords.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Proteínas da Mielina/imunologia , Receptores de Superfície Celular/imunologia , Traumatismos da Medula Espinal/terapia , Vacinas Sintéticas/uso terapêutico , Anticorpos Neutralizantes/imunologia , Humanos , Traumatismos da Medula Espinal/imunologia , Regeneração da Medula Espinal/imunologia
4.
J Neurosci ; 34(38): 12788-800, 2014 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-25232115

RESUMO

Combining cell transplantation with activity-based rehabilitation is a promising therapeutic approach for spinal cord repair. The present study was designed to investigate potential interactions between the transplantation (TP) of neural stem cells (NSCs) obtained at embryonic day 14 and treadmill training (TMT) in promoting locomotor recovery and structural repair in rat contusive injury model. Combination of TMT with NSC TP at 1 week after injury synergistically improved locomotor function. We report here that combining TMT increased the survival of grafted NSCs by >3-fold and >5-fold at 3 and 9 weeks after injury, respectively. The number of surviving NSCs was significantly correlated with the extent of locomotor recovery. NSCs grafted into the injured spinal cord were under cellular stresses induced by reactive nitrogen or oxygen species, which were markedly attenuated by TMT. TMT increased the concentration of insulin-like growth factor-1 (IGF-1) in the CSF. Intrathecal infusion of neutralizing IGF-1 antibodies, but not antibodies against either BDNF or Neurotrophin-3 (NT-3), abolished the enhanced survival of NSC grafts by TMT. The combination of TP and TMT also resulted in tissue sparing, increased myelination, and restoration of serotonergic fiber innervation to the lumbar spinal cord to a larger extent than that induced by either TP or TMT alone. Therefore, we have discovered unanticipated beneficial effects of TMT in modulating the survival of grafted NSCs via IGF-1. Our study identifies a novel neurobiological basis for complementing NSC-based spinal cord repair with activity-based neurorehabilitative approaches.


Assuntos
Fator de Crescimento Insulin-Like I/fisiologia , Atividade Motora/fisiologia , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplante , Transdução de Sinais , Traumatismos da Medula Espinal/reabilitação , Traumatismos da Medula Espinal/terapia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/imunologia , Sobrevivência Celular/imunologia , Sobrevivência Celular/fisiologia , Terapia Combinada/métodos , Feminino , Injeções Espinhais , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Região Lombossacral/inervação , Bainha de Mielina/metabolismo , Neurotrofina 3/imunologia , Ratos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Recuperação de Função Fisiológica/fisiologia , Neurônios Serotoninérgicos/fisiologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Regeneração da Medula Espinal/imunologia , Regeneração da Medula Espinal/fisiologia
5.
J Biol Chem ; 288(25): 18204-18, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23649623

RESUMO

Uncontrolled, excessive inflammation contributes to the secondary tissue damage of traumatic spinal cord, and HMGB1 is highlighted for initiation of a vicious self-propagating inflammatory circle by release from necrotic cells or immune cells. Several regenerative-competent vertebrates have evolved to circumvent the second damages during the spontaneous spinal cord regeneration with an unknown HMGB1 regulatory mechanism. By genomic surveys, we have revealed that two paralogs of HMGB1 are broadly retained from fish in the phylogeny. However, their spatial-temporal expression and effects, as shown in lowest amniote gecko, were tightly controlled in order that limited inflammation was produced in spontaneous regeneration. Two paralogs from gecko HMGB1 (gHMGB1) yielded distinct injury and infectious responses, with gHMGB1b significantly up-regulated in the injured cord. The intracellular gHMGB1b induced less release of inflammatory cytokines than gHMGB1a in macrophages, and the effects could be shifted by exchanging one amino acid in the inflammatory domain. Both intracellular proteins were able to mediate neuronal programmed apoptosis, which has been indicated to produce negligible inflammatory responses. In vivo studies demonstrated that the extracellular proteins could not trigger a cascade of the inflammatory cytokines in the injured spinal cord. Signal transduction analysis found that gHMGB1 proteins could not bind with cell surface receptors TLR2 and TLR4 to activate inflammatory signaling pathway. However, they were able to interact with the receptor for advanced glycation end products to potentiate oligodendrocyte migration by activation of both NFκB and Rac1/Cdc42 signaling. Our results reveal that HMGB1 does not mediate the inflammatory response in spontaneous spinal cord regeneration, but it promotes CNS regeneration.


Assuntos
Proteína HMGB1/metabolismo , Inflamação/metabolismo , Regeneração da Medula Espinal/fisiologia , Medula Espinal/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Apoptose/fisiologia , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , DNA Complementar/química , DNA Complementar/genética , Células HEK293 , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Lagartos , Camundongos , Microglia/imunologia , Microglia/metabolismo , Microscopia Confocal , Dados de Sequência Molecular , Neurônios/imunologia , Neurônios/metabolismo , Filogenia , Isoformas de Proteínas/classificação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Coelhos , Regeneração/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Medula Espinal/imunologia , Regeneração da Medula Espinal/genética , Regeneração da Medula Espinal/imunologia
6.
Mt Sinai J Med ; 78(2): 244-57, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21425268

RESUMO

Multiple sclerosis is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology. Conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability in multiple sclerosis patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes and reduce the rate of axonal transection. Studies in genetically modified animals have improved our understanding of mechanisms underlying central nervous system pathology in multiple sclerosis models, and have identified pathways that regulate oligodendrocyte viability and myelin repair. However, although clinical trials are ongoing, many have been unsuccessful, and no treatments are yet approved that target these areas in multiple sclerosis. In this review, we examine avenues for oligodendrocyte protection and endogenous myelin repair in animal models of demyelination and remyelination, and their relevance as therapeutics in human patients.


Assuntos
Redes Reguladoras de Genes/imunologia , Fatores Imunológicos , Esclerose Múltipla , Bainha de Mielina , Oligodendroglia , Regeneração da Medula Espinal/efeitos dos fármacos , Animais , Autoimunidade/efeitos dos fármacos , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Encefalomielite Autoimune Experimental , Humanos , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fármacos Neuroprotetores/uso terapêutico , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Regeneração da Medula Espinal/imunologia , Terapias em Estudo
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