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1.
Neuron ; 108(1): 128-144.e9, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32810432

RESUMO

Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that all somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor that is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that transcription factors induced early after peripheral nerve injury confer the cellular plasticity required for sensory neurons to transform into a regenerative state.


Assuntos
Fator 3 Ativador da Transcrição/genética , Reprogramação Celular/genética , Gânglios Espinais/citologia , Regulação da Expressão Gênica/genética , Neuralgia/genética , Traumatismos dos Nervos Periféricos/genética , Células Receptoras Sensoriais/metabolismo , Animais , Axônios , Axotomia , Lesões por Esmagamento/genética , Lesões por Esmagamento/metabolismo , Vértebras Lombares , Mecanorreceptores/metabolismo , Camundongos , Regeneração Nervosa , Plasticidade Neuronal/genética , Nociceptores/metabolismo , RNA-Seq , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Nervo Isquiático/cirurgia , Análise de Célula Única , Nervos Espinhais/lesões , Nervos Espinhais/cirurgia , Transcriptoma
2.
Exp Eye Res ; 190: 107859, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705897

RESUMO

The accumulation of chondroitin sulfate proteoglycans (CSPGs) in the glial scar following acute damage to the central nervous system (CNS) limits the regeneration of injured axons. Given the rich diversity of CSPG core proteins and patterns of GAG sulfation, identifying the composition of these CSPGs is essential for understanding their roles in injury and repair. Differential expression of core proteins and sulfation patterns have been characterized in the brain and spinal cord of mice and rats, but a comprehensive study of these changes following optic nerve injury has not yet been performed. Here, we show that the composition of CSPGs in the optic nerve and retina following optic nerve crush (ONC) in mice and rats exhibits an increase in aggrecan, brevican, phosphacan, neurocan and versican, similar to changes following spinal cord injury. We also observe an increase in inhibitory 4-sulfated (4S) GAG chains, which suggests that the persistence of CSPGs in the glial scar opposes the growth of CNS axons, thereby contributing to the failure of regeneration and recovery of function.


Assuntos
Lesões por Esmagamento/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Nervo Óptico/metabolismo , Retina/metabolismo , Agrecanas/metabolismo , Animais , Brevicam/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Glicosaminoglicanos/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Neurocam/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Sulfamonometoxina , Trimetoprima , Versicanas/metabolismo
3.
Eur Cytokine Netw ; 30(2): 59-66, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486397

RESUMO

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.


Assuntos
Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Animais , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
4.
Muscle Nerve ; 60(2): 192-201, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31093982

RESUMO

INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although muscle atrophy occurs very rapidly after nerve injury, the effect of 4-AP on muscle atrophy and intrinsic muscle contractile function is largely unknown. METHODS: Mice were assigned to sciatic nerve crush injury and no-injury groups and were followed for 3, 7, and 14 days with/without 4-AP or saline treatment. Morphological, functional, and transcriptional properties of skeletal muscle were assessed. RESULTS: In addition to improving in vivo function, 4-AP significantly reduced muscle atrophy with increased muscle fiber diameter and contractile force. Reduced muscle atrophy was associated with attenuated expression of atrophy-related genes and increased expression of proliferating stem cells. DISCUSSION: These findings provide new insights into the potential therapeutic benefits of 4-AP against nerve injury-induced muscle atrophy and dysfunction. Muscle Nerve 60: 192-201, 2019.


Assuntos
4-Aminopiridina/farmacologia , Lesões por Esmagamento/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Bloqueadores dos Canais de Potássio/farmacologia , Remielinização/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Animais , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Proteína Forkhead Box O1/efeitos dos fármacos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Camundongos , Proteínas Musculares/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/genética , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/patologia , Regeneração/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Proteínas com Motivo Tripartido/efeitos dos fármacos , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética
5.
Histochem Cell Biol ; 152(2): 89-107, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31093775

RESUMO

Recently, we evaluated capillary indices without discrimination by fiber type in rat extensor digitorum longus muscle (EDL) 4 weeks after nerve cut (NC), after double nerve crush (double NCR) and in two controls, from the start (CON-1) and the end (CON-2) of the experiment. In the present study, we determined the capillary indices related to specific myosin heavy chain (MyHC) fiber types. Fiber-type composition and local capillarity were assessed from a single, composite, multicolor image, where different MyHC-fiber types and capillaries were shown simultaneously. Applying local capillary indices [the number of capillaries around fiber (CAF) and the CAF scaled to fiber perimeter (CAF/FP)], to specific MyHC-fiber types, we found changes relevant to neuro-muscular studies. In the NC group, only type-2x fibers had a significantly lower CAF, and in the double NCR group, only type-2a fibers had a higher CAF in comparison with both controls. Both types of nerve injury elicited two responses: a coupled regulation of fiber size and capillarity in the oxidative, type 2a fibers and a capillarity independent regulation of fiber size in the glycolytic type-2b fibers. All subtypes of type-2 fibers had a better capillary supply (higher CAF/FP) in the NC and double NCR than in CON-2. The highest improvement was observed in type-2b fibers; this change was mirrored in an oxidative shift only in the double NCR group. Adopting fiber-type-specific capillary indices improves data analysis of rat EDL muscle samples.


Assuntos
Lesões por Esmagamento/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Animais , Ação Capilar , Lesões por Esmagamento/patologia , Lesões por Esmagamento/cirurgia , Masculino , Fibras Musculares Esqueléticas/química , Cadeias Pesadas de Miosina/análise , Procedimentos Neurocirúrgicos , Ratos , Ratos Wistar
6.
Andrology ; 6(6): 927-935, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30009463

RESUMO

Postradical prostatectomy erectile dysfunction (pRP-ED) is a major health issue. There has been a shortage of an effective treatment method until now. In this study, a total of 48 adult male Sprague-Dawley (SD) rats were randomly equally divided into four groups, including group 1-sham surgery with cavernous nerve exposure plus vehicle, group 2-bilateral cavernous nerve injury (BCNI) plus vehicle, group 3-BCNI plus adipose-derived mesenchymal stem cells (ADSCs)-derived exosomes (ADSC-Exo), and group 4-BCNI plus bone marrow-derived mesenchymal stem cell (BMSCs)-derived exosomes (BMSC-Exo). Twenty-one days following surgery, erectile function was measured before tissue harvest. Histologic and Western blot analyses were then performed. Exosomes were capable of internalization into human umbilical vein endothelial cells (HUVEC) in vitro and could be detected in the corpus cavernosum in vivo. The nNOS expression in the penile dorsal nerves (DN) and major pelvic ganglion (MPG), protein level of neurofilament in the DN, endothelial markers vWF, alpha smooth muscle actin (α-SMA), the ratio of smooth muscle to collagen content were obviously lower in BCNI group compared with the sham group, while ADSC-Exo and BMSC-Exo groups resulted in significant restoration of the above histopathological changes. Moreover, BCNI treated with ADSC-Exo or BMSC-Exo had significantly higher mean intracavernous pressure/mean arterial pressure ratio compared with BCNI group. The results demonstrated that both ADSC-Exo and BMSC-Exo treatment could significantly alleviate pathological changes and improve the erectile function in BCNI-related rats. Exosomes derived from ADSCs and BMSCs may be a potential agent for pRP-ED treatment.


Assuntos
Lesões por Esmagamento/cirurgia , Disfunção Erétil/cirurgia , Exossomos/transplante , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Ereção Peniana , Pênis/inervação , Traumatismos dos Nervos Periféricos/cirurgia , Tecido Adiposo/citologia , Animais , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Regeneração Nervosa , Óxido Nítrico Sintase Tipo I/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Fenótipo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Tempo
7.
Biomater Sci ; 6(8): 2059-2072, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-29932177

RESUMO

Non-viral vector gene delivery is generally limited by its potential toxicity problems, poor transfection abilities, serum stability, or relatively complex construction processes of modified polyplexes. Thus, we develop an efficient and stable polyplex system through convenient construction methods. Here, polyethyleneimine (PEI) 1.8 kDa and glutaraldehyde (GA) are used to construct a novel twice-condensed pDNA polyplex system using a one-pot construction method, including pH-responsive C[double bond, length as m-dash]N linkages by which different PEI molecules on one single polyplex can link with each other. In this system, smaller particle sizes, higher zeta potentials and better serum stabilities are achieved without PEGylation or other chemical modifications using lyophobic segments, but via pH-responsive linkages that ensure the escape of nucleic acids. This polyplex system is used to deliver the pDNA of vascular endothelial growth factor (VEGF) whose half-life period in vivo is only around 30 minutes. Compared with polyplexes prepared using PEI 25 kDa, cells and rats treated with twice-condensed VEGF pDNA polyplexes express significantly more VEGF or myelin basic protein (MBP), and this new polyplex system showed fewer adverse effects in vitro and in vivo. In addition, revascularization and neurogenesis are also discovered in the rat sciatic nerve crush injury model.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , DNA/química , Glutaral/farmacologia , Polietilenoimina/farmacologia , Nervo Isquiático/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , DNA/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Transferência de Genes , Glutaral/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Bloqueio Nervoso , Tamanho da Partícula , Plasmídeos/química , Plasmídeos/genética , Polietilenoimina/química , Ratos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Relação Estrutura-Atividade , Fatores de Crescimento do Endotélio Vascular/química , Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Anat Rec (Hoboken) ; 301(10): 1646-1656, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29710417

RESUMO

Vascular endothelial growth factor (VEGF) represents one of the main factors involved not only in angiogenesis and vasculogenesis but also in neuritogenesis. VEGF plays its function acting via different receptors: VEGF receptor1 (VEGFR-1), VEGF receptor2 (VEGFR-2), VEGF receptor3 (VEGFR-3), and co-receptors Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). This study reports on the first in vivo analysis of the expression of VEGF and VEGF family molecules in peripheral nerve degeneration and regeneration: for this purpose, different models of nerve lesion in rat were adopted, the median nerve crush injury and the median nerve transaction followed or not by end-to end microsurgical repair. Results obtained by real time polymerase chain reaction showed that VEGF and VEGF family molecules are differentially expressed under regenerating and degenerating condition, furthermore, in order to study the modulation and involvement of these factors in two different regenerative models, crush injury and end-to-end repair, protein expression analysis was evaluated. In addition, immunohistochemical analysis allowed to state a glial localization of VEGF and VEGFR-2 after peripheral nerve crush injury. Finally in vitro assay on primary Schwann cells culture show that VEGF165 stimulation increases Schwann cells migration, a major process in the promotion of neurite outgrowth. Anat Rec, 301:1646-1656, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Lesões por Esmagamento/metabolismo , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Denervação , Regulação para Baixo , Feminino , Nervo Mediano/lesões , Neuropatia Mediana/metabolismo , Neuropilina-1/metabolismo , Neuropilina-2/metabolismo , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/farmacologia
9.
J Hand Surg Asian Pac Vol ; 22(4): 464-471, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29117831

RESUMO

BACKGROUND: Schwann cells are integral to the regenerative capacity of the peripheral nervous system, which declines after adolescence. The mechanisms underlying this decline are poorly understood. This study sought to compare the protein expression of Notch, c-Jun, and Krox-20 after nerve crush injury in adolescent and young adult rats. We hypothesized that these Schwann cell myelinating regulatory factors are down-regulated after nerve injury in an age-dependent fashion. METHODS: Adolescent (2 months old) and young adult (12 months old) rats (n = 48) underwent sciatic nerve crush injury. Protein expression of Notch, c-Jun, and Krox-20 was quantified by Western blot analysis at 1, 3, and 7 days post-injury. Functional recovery was assessed in a separate group of animals (n = 8) by gait analysis (sciatic functional index) and electromyography (compound motor action potential) over an 8-week post-injury period. RESULTS: Young adult rats demonstrated a trend of delayed onset of the dedifferentiating regulatory factors, Notch and c-Jun, corresponding to the delayed functional recovery observed in young adult rats compared to adolescent rats. Compound motor action potential area was significantly greater in adolescent rats relative to young adult rats, while amplitude and velocity trended toward statistical significance. CONCLUSIONS: The process of Schwann cell dedifferentiation following peripheral nerve injury shows different trends with age. These trends of delayed onset of key regulatory factors responsible for Schwann cell myelination may be one of many possible factors mediating the significant differences in functional recovery between adolescent and young adult rats following peripheral nerve injury.


Assuntos
Desdiferenciação Celular , Células de Schwann/citologia , Nervo Isquiático/lesões , Potenciais de Ação , Fatores Etários , Animais , Lesões por Esmagamento/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Modelos Animais , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos Endogâmicos F344 , Receptores Notch/metabolismo , Recuperação de Função Fisiológica , Nervo Isquiático/metabolismo
10.
Brain Res ; 1669: 69-78, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28554806

RESUMO

Preventing damage caused by nerve degeneration is a great challenge. There is a growing body of evidence implicating extracellular nucleotides and their P2 receptors in many pathophysiological mechanisms. In this work we aimed to investigate the effects of the administration of Brilliant Blue G (BBG) and Pyridoxalphosphate-6-azophenyl-2', 4'- disulphonic acid (PPADS), P2X7 and P2 non-selective receptor antagonists, respectively, on sciatic nerve regeneration. Four groups of mice that underwent nerve crush lesion were used: two control groups treated with vehicle (saline), a group treated with BBG and a group treated with PPADS during 28days. Gastrocnemius muscle weight was evaluated. For functional evaluation we used the Sciatic Functional Index (SFI) and the horizontal ladder walking test. Nerves, dorsal root ganglia and spinal cords were processed for light and electron microscopy. Antinoceptive effects of BBG and PPADS were evaluated through von Frey E, and the levels of IL-1ß and TNF-α were analyzed by ELISA. BBG promoted an increase in the number of myelinated fibers and on axon, fiber and myelin areas. BBG and PPADS led to an increase of TNF-α and IL-1ß in the nerve on day 1 and PPADS caused a decrease of IL-1ß on day 7. Mechanical allodynia was reversed on day 7 in the groups treated with BBG and PPADS. We concluded that BBG promoted a better morphological regeneration after ischiatic crush injury, but this was not followed by anticipation of functional improvement. In addition, both PPADS and BBG presented anti-inflammatory as well as antinociceptive effects.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Analgésicos/farmacologia , Animais , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Modelos Animais de Doenças , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Interleucina-1alfa/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Distribuição Aleatória , Receptores Purinérgicos P2X7/metabolismo , Corantes de Rosanilina/farmacologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/metabolismo
11.
Stem Cells Transl Med ; 6(2): 458-470, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28191764

RESUMO

Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva-derived MSCs (GMSCs) could be directly induced into multipotent NPCs (iNPCs) under minimally manipulated conditions without the introduction of exogenous genes. Using a crush-injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells. After crush injury, iNPCs, compared with GMSCs, displayed superior therapeutic effects on axonal regeneration at both the injury site and the distal segment of the injured sciatic nerve. Mechanistically, transplantation of GMSCs, especially iNPCs, significantly attenuated injury-triggered increase in the expression of c-Jun, a transcription factor that functions as a major negative regulator of myelination and plays a central role in dedifferentiation/reprogramming of Schwann cells into a progenitor-like state. Meanwhile, our results also demonstrate that transplantation of GMSCs and iNPCs consistently increased the expression of Krox-20/EGR2, a transcription factor that governs the expression of myelin proteins and facilitates myelination. Altogether, our findings suggest that transplantation of GMSCs and iNPCs promotes peripheral nerve repair/regeneration, possibly by promoting remyelination of Schwann cells mediated via the regulation of the antagonistic myelination regulators, c-Jun and Krox-20/EGR2. Stem Cells Translational Medicine 2017;6:458-470.


Assuntos
Lesões por Esmagamento/cirurgia , Gengiva/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Bainha de Mielina/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/transplante , Remielinização , Células de Schwann/metabolismo , Nervo Isquiático/cirurgia , Neuropatia Ciática/cirurgia , Animais , Diferenciação Celular , Separação Celular , Células Cultivadas , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Fenótipo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos Sprague-Dawley , Células de Schwann/patologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Transdução de Sinais
12.
J Cell Biol ; 216(2): 495-510, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28137778

RESUMO

Loss of the Merlin tumor suppressor and activation of the Hippo signaling pathway play major roles in the control of cell proliferation and tumorigenesis. We have identified completely novel roles for Merlin and the Hippo pathway effector Yes-associated protein (YAP) in the control of Schwann cell (SC) plasticity and peripheral nerve repair after injury. Injury to the peripheral nervous system (PNS) causes a dramatic shift in SC molecular phenotype and the generation of repair-competent SCs, which direct functional repair. We find that loss of Merlin in these cells causes a catastrophic failure of axonal regeneration and remyelination in the PNS. This effect is mediated by activation of YAP expression in Merlin-null SCs, and loss of YAP restores axonal regrowth and functional repair. This work identifies new mechanisms that control the regenerative potential of SCs and gives new insight into understanding the correct control of functional nerve repair in the PNS.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Lesões por Esmagamento/metabolismo , Regeneração Nervosa , Neurofibromina 2/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Neuropatia Ciática/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Axônios/metabolismo , Axônios/patologia , Proteínas de Ciclo Celular , Lesões por Esmagamento/genética , Lesões por Esmagamento/patologia , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Feminino , Genótipo , Masculino , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Atividade Motora , Bainha de Mielina/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurofibromina 2/deficiência , Neurofibromina 2/genética , Plasticidade Neuronal , Fenótipo , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Recuperação de Função Fisiológica , Células de Schwann/patologia , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/genética , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Transdução de Sinais , Fatores de Tempo
13.
Ultrasound Med Biol ; 43(2): 461-468, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27816247

RESUMO

Low-intensity ultrasound (LIU) can improve nerve regeneration and functional recovery after peripheral nerve crush injury, but the underlying mechanism is not clear. The objective of this study was to examine the effects of LIU on rat sciatic crush injury and to investigate a possible molecular mechanism. Adult male Sprague-Dawley rats underwent left sciatic nerve crush surgery and were then randomized into two groups: a treatment group that received LIU every other d, and a control group that received sham exposure. Compared with rats in the control group, rats in the treatment group had higher sciatic nerve function indexes, compound muscle action potentials, wet weight ratios of the target muscle and mRNA expression of brain-derived neurotropic factor (BDNF) in the crushed nerve and ipsilateral dorsal root ganglia. Our findings suggest that LIU might promote injured nerve regeneration by stimulating BDNF release.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lesões por Esmagamento/terapia , Nervo Isquiático/lesões , Terapia por Ultrassom/métodos , Animais , Lesões por Esmagamento/metabolismo , Modelos Animais de Doenças , Masculino , Regeneração Nervosa/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia
14.
Transplantation ; 101(7): 1573-1586, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27607534

RESUMO

BACKGROUND: Reinnervation timing after nerve injury is critical for favorable axonal regeneration, remyelination, and clinical improvement. Considering bone marrow mononuclear cells (BMMC) are easily obtained and readily available for transplant, this work analyzed the effect of BMMC systemic administration on nerve repair and pain behavior. METHODS: Adult rats with sciatic nerve crush were immediately and systemically injected BMMC through the caudal artery. Nontreated, sham and naïve rats were also included. Histological, immunohistochemical, biochemical, functional, and behavioral analyses were performed in nerves harvested from each group at different survival times. RESULTS: Axons in BMMC-treated rats exhibited a more conserved morphological appearance than those in nontreated rats, as observed at different survival times both in semithin sections and ultrastructural analysis. BMMC-treated rats also showed a reduction in major myelin protein immunoreactive clusters 7 and 14 days postinjury, as compared with nontreated rats. Electrophysiological analysis showed BMMC treatment to slightly improve the amplitude of compound muscle action potential starting at 14 days postinjury. Finally, mechanical withdrawal threshold revealed a full preventive action against transient mechanical hypersensitivity in BMMC-treated rats. CONCLUSIONS: These data demonstrate the efficiency of BMMC, systemically and noninvasively transplanted, in correcting morphological, functional and behavioral alterations resulting from peripheral nerve injury.


Assuntos
Analgesia/métodos , Axônios/patologia , Transplante de Medula Óssea/métodos , Lesões por Esmagamento/cirurgia , Hiperalgesia/prevenção & controle , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/cirurgia , Nervo Isquiático/cirurgia , Degeneração Walleriana , Animais , Axônios/metabolismo , Biomarcadores/metabolismo , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Lesões por Esmagamento/fisiopatologia , Modelos Animais de Doenças , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Bainha de Mielina/metabolismo , Limiar da Dor , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos Wistar , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Fatores de Tempo
15.
J Tissue Eng Regen Med ; 11(5): 1619-1629, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-26876895

RESUMO

In the present study we evaluated the motor recovery process of peripheral nerve injury (PNI), based on electrophysiological and histomorphometric criteria, after treatment with plasma rich in growth factors (PRGF) injections and scaffolds in an ovine model. Three groups of sheep underwent a nerve crush lesion: the first group (n = 3) was left to recover spontaneously (SR); the second group was administered saline injections (SI; n = 5) and a third group (n = 6) received PRGF injections and scaffolds immediately after the crush injury. At post-intervention week 8, 70% of sheep in the PRGF group were CMAP-positive, with no electrophysiological response in the rest of the groups. Histomorphometric analysis 12 weeks after the surgical intervention revealed that the average axonal density of the SR (1184 ± 864 axons/µm2 ) and SI (3109 ± 2450 axons/µm2 ) groups was significantly inferior to the control (8427 ± 2433 axons/µm2 ) and also inferior to the PRGF group (5276 ± 4148 axons/µm2 ), showing no significant differences between the control and PRGF groups. The axonal size of the SR and SI groups was significantly smaller compared with the control group (18 ± 4 µm2 ), whereas the axonal size of the PRGF group (6 ± 5 µm2 ) did not show statistical differences from the control. Morphometry of the target muscles indicated that the PRGF group had the lowest percentage volume reduction 12 weeks after the crush injury. The PRGF group had larger muscle fibre areas than the SI and SR groups, although the differences did not reach statistical significance. Overall, these data suggest that the PRGF injections and scaffolds hastened functional axon recovery and dampened atrophy of the target muscles in an ovine model. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Lesões por Esmagamento/terapia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Traumatismos dos Nervos Periféricos/terapia , Nervos Periféricos/metabolismo , Plasma , Tecidos Suporte , Ondas Ultrassônicas , Animais , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Nervos Periféricos/patologia , Ovinos
16.
J Nutr Biochem ; 38: 102-106, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27732910

RESUMO

Peripheral nervous injury (PNI) is a common form of trauma in modern society, especially in sport players. Despite the advance of therapy for PNI, the recovery of function can never reach the preinjury level after treatments. Recently, inhibiting neural oxidative stress shows a beneficial effect in improving functional recovery after PNI. In addition, sesame oil has been reported to possess the excellent antioxidative properties. However, whether sesame oil can improve the functional recovery after PNI by its antioxidative effect has never been investigated. Thirty mice were randomly divided into five groups of six: group I mice received sham operation; group II mice received sciatic nerve crush; and groups III-V mice daily ingested 0.5, 1 and 2 ml/kg of sesame oil for 6 days, respectively, after sciatic nerve crush. Oxidative stress, GAP43 and nuclear Nrf2 levels as well as spinal somatosensory evoked potentials were assessed on day 6, while paw withdrawal latency and sciatic function index were assessed on days 0, 3, and 6. Sesame oil significantly decreased lipid peroxidation and increased nuclear factor erythroid 2-related factor 2 and GAP43 expression in sciatic nerve. Furthermore, sesame oil improved electrophysiological and functional assessments in mice with sciatic nerve crush. In conclusion, sesame oil may improve nerve functional recovery by attenuating nerve oxidative stress in mouse acute peripheral nerve injury. Further, application of natural product sesame oil may be an alternative approach for improving nerve functional recovery in the clinical setting.


Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Fator 2 Relacionado a NF-E2/agonistas , Estresse Oxidativo , Traumatismos dos Nervos Periféricos/dietoterapia , Nervo Isquiático/lesões , Óleo de Gergelim/uso terapêutico , Transporte Ativo do Núcleo Celular , Animais , Antioxidantes/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Lesões por Esmagamento/dietoterapia , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/fisiopatologia , Potenciais Somatossensoriais Evocados , Proteína GAP-43/agonistas , Proteína GAP-43/metabolismo , Peroxidação de Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/metabolismo , Medição da Dor , Traumatismos dos Nervos Periféricos/sangue , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Distribuição Aleatória , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Óleo de Gergelim/administração & dosagem , Organismos Livres de Patógenos Específicos
18.
Int J Mol Med ; 37(5): 1170-80, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26986762

RESUMO

The use of mesenchymal stem cells (MSCs) in cell therapy in regenerative medicine has great potential, particularly in the treatment of nerve injury. Umbilical cord blood (UCB) reportedly contains stem cells, which have been widely used as a hematopoietic source and may have therapeutic potential for neurological impairment. Although ongoing research is dedicated to the management of traumatic optic nerve injury using various measures, novel therapeutic strategies based on the complex underlying mechanisms responsible for optic nerve injury, such as inflammation and/or ischemia, are required. In the present study, a rat model of optic nerve crush (ONC) injury was established in order to examine the effects of transplanting human chorionic plate-derived MSCs (CP­MSCs) isolated from the placenta, as well as human UCB mononuclear cells (CB-MNCs) on compressed rat optic nerves. Expression markers for inflammation, apoptosis, and optic nerve regeneration were analyzed, as well as the axon survival rate by direct counting. Increased axon survival rates were observed following the injection of CB­MNCs at at 1 week post-transplantation compared with the controls. The levels of growth-associated protein-43 (GAP­43) were increased after the injection of CB­MNCs or CP­MSCs compared with the controls, and the expression levels of hypoxia-inducible factor-1α (HIF-1α) were also significantly increased following the injection of CB-MNCs or CP-MSCs. ERM-like protein (ERMN) and SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2) were found to be expressed in the optic nerves of the CP­MSC-injected rats with ONC injury. The findings of our study suggest that the administration of CB­MNCs or CP­MSCs may promote axon survival through systemic concomitant mechanisms involving GAP­43 and HIF­1α. Taken together, these findings provide further understanding of the mechanisms repsonsible for optic nerve injury and may aid in the development of novel cell-based therapeutic strategies with future applications in regenerative medicine, particularly in the management of optic nerve disorders.


Assuntos
Axônios/metabolismo , Lesões por Esmagamento/metabolismo , Sangue Fetal/citologia , Leucócitos Mononucleares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regeneração Nervosa , Traumatismos do Nervo Óptico/metabolismo , Animais , Biomarcadores , Sobrevivência Celular , Lesões por Esmagamento/genética , Lesões por Esmagamento/patologia , Feminino , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunofenotipagem , Leucócitos Mononucleares/transplante , Masculino , Transplante de Células-Tronco Mesenquimais , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/patologia , Fenótipo , Gravidez , Ratos
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