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1.
Cell Death Dis ; 13(5): 432, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504882

RESUMO

Neuroinflammation is regarded as a vital pathological process in spinal cord injury (SCI), which removes damaged tissue, secretes cytokines, and facilitates regeneration. Repopulation of microglia has been shown to favor recovery from SCI. However, the origin and regulatory factors of microglia repopulation after SCI remain unknown. Here, we used single-cell RNA sequencing to portray the dynamic transcriptional landscape of immune cells during the early and late phases of SCI in mice. B cells and migDCs, located in the meninges under physiological conditions, are involved in immune surveillance. Microglia quickly reduced, and peripheral myeloid cells infiltrated three days-post-injury (dpi). At 14 dpi, microglia repopulated, myeloid cells were reduced, and lymphocytes infiltrated. Importantly, genetic lineage tracing of nestin+ and Cx3cr1+ cells in vivo showed that the repopulation of microglia was derived from residual microglia after SCI. We found that residual microglia regress to a developmental growth state in the early stages after SCI. Hif1α promotes microglial proliferation. Conditional ablation of Hif1α in microglia causes larger lesion sizes, fewer axon fibers, and impaired functional recovery in the late stages after SCI. Our results mapped the immune heterogeneity in SCI and raised the possibility that targeting Hif1α may help in axon regeneration and functional recovery after SCI.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Axônios/patologia , Perfilação da Expressão Gênica , Camundongos , Microglia/patologia , Regeneração Nervosa/genética , Traumatismos da Medula Espinal/patologia
2.
Spinal Cord Ser Cases ; 8(1): 51, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534465

RESUMO

INTRODUCTION: Chronic irritation caused by urinary catheter may predispose to metaplastic changes in the bladder and very rarely, nephrogenic metaplasia. CASE PRESENTATION: A 53-year-old lady with T-2 paraplegia and urethral catheter drainage for 27 years presented with haematuria. MRI of pelvis, performed seven years ago, showed a 10 cm intramural fibroid within the anterior aspect of the uterine body which was pushing the collapsed urinary bladder containing the Foley catheter to the left. The patient decided to avoid surgery to remove the fibroid at that time. Ultrasound scan of the urinary bladder done now, revealed a polypoidal lesion in the left superolateral wall. Superficial enhancing lesion with no invasion of the bladder wall was seen in the CT urography. Cystoscopy showed extensive catheter reaction, and in the centre, a slightly more papillary area, which was resected. Histology revealed inflamed bladder mucosa showing tubular and papillary structures lined by cuboidal epithelial cells; the features were of nephrogenic metaplasia. The tubular and papillary structures were lined by cells showing positive immunohistochemical staining for CK7 and PAX8. DISCUSSION: Catheter reaction and nephrogenic metaplasia was found in the left superolateral wall of the bladder where the large uterine fibroid was pushing the balloon of the catheter against the bladder wall for more than seven years. The patient decided to undergo surgery to remove the large fibroid and thereby prevent further pressure effects upon the urinary bladder.


Assuntos
Leiomioma , Traumatismos da Medula Espinal , Feminino , Humanos , Leiomioma/patologia , Metaplasia/patologia , Pessoa de Meia-Idade , Paraplegia , Traumatismos da Medula Espinal/patologia , Bexiga Urinária/patologia
3.
Nat Neurosci ; 25(5): 617-629, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35524138

RESUMO

Severe spinal cord injury in adults leads to irreversible paralysis below the lesion. However, adult rodents that received a complete thoracic lesion just after birth demonstrate proficient hindlimb locomotion without input from the brain. How the spinal cord achieves such striking plasticity remains unknown. In this study, we found that adult spinal cord injury prompts neurotransmitter switching of spatially defined excitatory interneurons to an inhibitory phenotype, promoting inhibition at synapses contacting motor neurons. In contrast, neonatal spinal cord injury maintains the excitatory phenotype of glutamatergic interneurons and causes synaptic sprouting to facilitate excitation. Furthermore, genetic manipulation to mimic the inhibitory phenotype observed in excitatory interneurons after adult spinal cord injury abrogates autonomous locomotor functionality in neonatally injured mice. In comparison, attenuating this inhibitory phenotype improves locomotor capacity after adult injury. Together, these data demonstrate that neurotransmitter phenotype of defined excitatory interneurons steers locomotor recovery after spinal cord injury.


Assuntos
Interneurônios , Traumatismos da Medula Espinal , Animais , Interneurônios/fisiologia , Locomoção/fisiologia , Camundongos , Neurotransmissores , Fenótipo , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
4.
Nat Commun ; 13(1): 1959, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35414131

RESUMO

The spinal cord accounts for the main communication pathway between the brain and the peripheral nervous system. Spinal cord injury is a devastating and largely irreversible neurological trauma, and can result in lifelong disability and paralysis with no available cure. In vivo spinal cord imaging in mouse models without introducing immunological artifacts is critical to understand spinal cord pathology and discover effective treatments. We developed a minimally invasive intervertebral window by retaining the ligamentum flavum to protect the underlying spinal cord. By introducing an optical clearing method, we achieve repeated two-photon fluorescence and stimulated Raman scattering imaging at subcellular resolution with up to 15 imaging sessions over 6-167 days and observe no inflammatory response. Using this optically cleared intervertebral window, we study neuron-glia dynamics following laser axotomy and observe strengthened contact of microglia with the nodes of Ranvier during axonal degeneration. By enabling long-term, repetitive, stable, high-resolution and inflammation-free imaging of mouse spinal cord, our method provides a reliable platform in the research aiming at interpretation of spinal cord physiology and pathology.


Assuntos
Traumatismos da Medula Espinal , Animais , Diagnóstico por Imagem , Modelos Animais de Doenças , Camundongos , Microglia/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
5.
J Neuroinflammation ; 19(1): 95, 2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35429978

RESUMO

BACKGROUND: Excessively deposited fibrotic scar after spinal cord injury (SCI) inhibits axon regeneration. It has been reported that platelet-derived growth factor receptor beta (PDGFRß), as a marker of fibrotic scar-forming fibroblasts, can only be activated by platelet-derived growth factor (PDGF) B or PDGFD. However, whether the activation of the PDGFRß pathway can mediate fibrotic scar formation after SCI remains unclear. METHODS: A spinal cord compression injury mouse model was used. In situ injection of exogenous PDGFB or PDGFD in the spinal cord was used to specifically activate the PDGFRß pathway in the uninjured spinal cord, while intrathecal injection of SU16f was used to specifically block the PDGFRß pathway in the uninjured or injured spinal cord. Immunofluorescence staining was performed to explore the distributions and cell sources of PDGFB and PDGFD, and to evaluate astrocytic scar, fibrotic scar, inflammatory cells and axon regeneration after SCI. Basso Mouse Scale (BMS) and footprint analysis were performed to evaluate locomotor function recovery after SCI. RESULTS: We found that the expression of PDGFD and PDGFB increased successively after SCI, and PDGFB was mainly secreted by astrocytes, while PDGFD was mainly secreted by macrophages/microglia and fibroblasts. In addition, in situ injection of exogenous PDGFB or PDGFD can lead to fibrosis in the uninjured spinal cord, while this profibrotic effect could be specifically blocked by the PDGFRß inhibitor SU16f. We then treated the mice after SCI with SU16f and found the reduction of fibrotic scar, the interruption of scar boundary and the inhibition of lesion and inflammation, which promoted axon regeneration and locomotor function recovery after SCI. CONCLUSIONS: Our study demonstrates that activation of PDGFRß pathway can directly induce fibrotic scar formation, and specific blocking of this pathway would contribute to the treatment of SCI.


Assuntos
Axônios , Cicatriz , Indóis , Regeneração Nervosa , Pirróis , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Traumatismos da Medula Espinal , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Cicatriz/tratamento farmacológico , Cicatriz/etiologia , Cicatriz/metabolismo , Cicatriz/patologia , Fibrose , Indóis/farmacologia , Locomoção , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Proteínas Proto-Oncogênicas c-sis/metabolismo , Pirróis/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
6.
Medicine (Baltimore) ; 101(16): e29188, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35482988

RESUMO

RATIONALE: Surfer's myelopathy is a rare atraumatic spinal cord injury most frequently experienced by novice surfers. Patients often experience back pain, followed by motor, sensory, bowel, and bladder involvement. Here, we report a case of surfer's myelopathy. PATIENT CONCERNS: The patient presented with acute low back pain associated with lower limb weakness, sensory loss, urinary retention, and perineal paraesthesia 1 hour after her first surf lesson. DIAGNOSIS: On arrival at the emergency department, she was noted to have flaccid paralysis with flickers in both lower limbs, reduced sensation in the midthoracic region, reduced anal tone, and saddle anesthesia. Magnetic resonance imaging of the spine revealed evidence of restricted diffusion from T6 to the level of the conus. Extensive investigations, including cerebrospinal fluid analysis, vasculitides/paraneoplastic screening, and further imaging, were unremarkable. She was diagnosed with complete T7 spinal cord injury secondary to surfer's myelopathy. INTERVENTIONS: She subsequently received methylprednisolone and was transferred to the spinal injury unit for rehabilitation. As she experienced persistent neuropathic pain at the level of the injury, she received input from the local pain team. One month after the injury, the patient developed swelling of the right thigh associated with reduced internal and external rotation of the right hip, impacting rehabilitation. The patient was diagnosed with heterotopic ossification following a triple-phase bone scan. She then received intravenous zolendronic acid, which had a good effect. OUTCOMES: Four months after the initial presentation, she was discharged to the community. Despite no improvement in her neurological status, she was independent of transfers and mobility with a wheelchair. In addition, she managed her neurogenic bowel and bladder independently with intermittent self-catheterization and a transanal irrigation system. At 6 months, she engaged well with returning to drive program and vocational rehabilitation. LESSONS: Neurological recovery from surfer's myelopathy has been shown to vary from complete recovery to minimal recovery. With a spinal-specific rehabilitation program, this patient remains independent of her activities of daily living. Surfer's myelopathy often occurs in inexperienced surfers; therefore, it is crucial to provide education to surfers and instructors.


Assuntos
Doenças da Medula Espinal , Traumatismos da Medula Espinal , Atividades Cotidianas , Viroses do Sistema Nervoso Central , Feminino , Humanos , Mielite , Doenças Neuromusculares , Doenças da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/patologia , Tomografia Computadorizada por Raios X
7.
Ulus Travma Acil Cerrahi Derg ; 28(3): 233-241, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35485570

RESUMO

BACKGROUND: Annona muricata (AM) (graviola) is a plant that grows in tropical regions and is thought to be good for many diseases by local people. Unfortunately, there is no acceptable medical treatment for spinal cord injury (SCI) yet. In our study, we investigated the neuropeotective effects of AM leaf extract on SCI in an experimental rat model. METHODS: A total of 40 Wistar albino rats were randomly divided into five equal groups (n=8). Group 1 was the control group in which only laminectomy was performed. Trauma was induced in four groups after laminectomy. Group 2 (untreated trauma group) was given no medication. In Group 3, a single intraperitoneal dose of methylprednisolone (30 mg/kg) was administered after trauma. The rats in Groups 4 received a low dose (100 mg/kg) of AM leaf extracts by oral gavage one week before trauma while the rats in Group 5 received a high-dose (300 mg/kg) of these extracts by oral gavage one week before trauma. All rats, including the control group, were sacrificed 24 h after the trauma was created. RESULTS: Tissue samples taken to evaluate the neuroprotective effect were examined biochemically and histopathologically. Inflam-matory findings in the trauma group were significantly better in both groups treated with AM. There was no difference between the groups in terms of clinical motor examination and inclined plane test results. CONCLUSION: Our histopathological and biochemical results showed that AM is an agent with neuroprotective effects in trau-matic SCI.


Assuntos
Annona , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Animais , Humanos , Metilprednisolona/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
8.
J Neuroinflammation ; 19(1): 102, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488301

RESUMO

BACKGROUND: Spinal cord injury (SCI) elicits a robust neuroinflammatory reaction which, in turn, exacerbates the initial mechanical damage. Pivotal players orchestrating this response are macrophages (Mφs) and microglia. After SCI, the inflammatory environment is dominated by pro-inflammatory Mφs/microglia, which contribute to secondary cell death and prevent regeneration. Therefore, reprogramming Mφ/microglia towards a more anti-inflammatory and potentially neuroprotective phenotype has gained substantial therapeutic interest in recent years. Interleukin-13 (IL-13) is a potent inducer of such an anti-inflammatory phenotype. In this study, we used genetically modified Mφs as carriers to continuously secrete IL-13 (IL-13 Mφs) at the lesion site. METHODS: Mφs were genetically modified to secrete IL-13 (IL-13 Mφs) and were phenotypically characterized using qPCR, western blot, and ELISA. To analyze the therapeutic potential, the IL-13 Mφs were intraspinally injected at the perilesional area after hemisection SCI in female mice. Functional recovery and histopathological improvements were evaluated using the Basso Mouse Scale score and immunohistochemistry. Neuroprotective effects of IL-13 were investigated using different cell viability assays in murine and human neuroblastoma cell lines, human neurospheroids, as well as murine organotypic brain slice cultures. RESULTS: In contrast to Mφs prestimulated with recombinant IL-13, perilesional transplantation of IL-13 Mφs promoted functional recovery following SCI in mice. This improvement was accompanied by reduced lesion size and demyelinated area. The local anti-inflammatory shift induced by IL-13 Mφs resulted in reduced neuronal death and fewer contacts between dystrophic axons and Mφs/microglia, suggesting suppression of axonal dieback. Using IL-4Rα-deficient mice, we show that IL-13 signaling is required for these beneficial effects. Whereas direct neuroprotective effects of IL-13 on murine and human neuroblastoma cell lines or human neurospheroid cultures were absent, IL-13 rescued murine organotypic brain slices from cell death, probably by indirectly modulating the Mφ/microglia responses. CONCLUSIONS: Collectively, our data suggest that the IL-13-induced anti-inflammatory Mφ/microglia phenotype can preserve neuronal tissue and ameliorate axonal dieback, thereby promoting recovery after SCI.


Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Animais , Feminino , Humanos , Interleucina-13/uso terapêutico , Macrófagos/metabolismo , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/patologia
9.
Cell Death Dis ; 13(4): 381, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35444186

RESUMO

The pathogenic mechanisms that underlie the progression of remote degeneration after spinal cord injury (SCI) are not fully understood. In this study, we examined the relationship between endoplasmic reticulum (ER) stress and macroautophagy, hereafter autophagy, and its contribution to the secondary damage and outcomes that are associated with remote degeneration after SCI. Using a rat model of spinal cord hemisection at the cervical level, we measured ER stress and autophagy markers in the axotomized neurons of the red nucleus (RN). In SCI animals, mRNA and protein levels of markers of ER stress, such as GRP78, CHOP, and GADD34, increased 1 day after the injury, peaking on Day 5. Notably, in SCI animals, the increase of ER stress markers correlated with a blockade in autophagic flux, as evidenced by the increase in microtubule-associated protein 2 light chain 3 (LC3-II) and p62/SQSTM1 (p62) and the decline in LAMP1 and LAMP2 levels. After injury, treatment with guanabenz protected neurons from UPR failure and increased lysosomes biogenesis, unblocking autophagic flux. These effects correlated with greater activation of TFEB and improved neuronal survival and functional recovery-effects that persisted after suspension of the treatment. Collectively, our results demonstrate that in remote secondary damage, impairments in autophagic flux are intertwined with ER stress, an association that contributes to the apoptotic cell death and functional damage that are observed after SCI.


Assuntos
Autofagossomos , Traumatismos da Medula Espinal , Animais , Apoptose , Autofagossomos/metabolismo , Autofagia , Estresse do Retículo Endoplasmático , Proteostase , Ratos , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
10.
Oxid Med Cell Longev ; 2022: 1724362, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35387259

RESUMO

Spinal cord injury (SCI) often results in damage to or degeneration of axons. Crosstalk between astrocytes and neurons plays a pivotal role in neurite outgrowth following SCI. Rehabilitative training is a recognized method for the treatment of SCI, but the specific mechanism underlying its effect on axonal outgrowth in the central nervous system (CNS) has not yet been determined. A total of 190 adult male SD rats weighing 200-250 g were randomly divided into eight groups for use as animal models of SCI. Rats were subjected to water treadmill training (TT) for 7 or 14 d. The Basso-Beattie-Bresnahan (BBB) motor function scale, hematoxylin-eosin (HE) staining, Nissl staining, Western blotting, and immunofluorescence were used to measure tissue morphology and the degree of neurological deficit and to determine quantitative expression and accurate localization of the corresponding proteins. We found that TT decreased tissue structure damage and improved functional recovery. TT also promoted the regeneration of neurons and reduced SCI-induced apoptosis SCI around the lesion, as well as significantly increasing the expression of GAP43 and NF200 after SCI. In addition, TT significantly inhibited the injury-induced increase in the expression of proinflammatory factors. Moreover, TT reduced the activation of astrocytes and microglia, accompanied by the reduced expression of C3d and increased expression of S100A10. Finally, TT effectively reduced the level of chondroitin sulfate proteoglycan (CSPG) surrounding the lesion and inhibited the NGR/RhoA/ROCK signaling pathway in neurons after SCI. Overall, we found that TT played a novel role in recovery from SCI by promoting axonal outgrowth associated with NGR/RhoA/ROCK signaling by inhibiting astrocyte activation after SCI.


Assuntos
Astrócitos , Traumatismos da Medula Espinal , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Masculino , Crescimento Neuronal , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Água/farmacologia
11.
Exp Neurol ; 352: 114035, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35276206

RESUMO

Spinal cord injuries (SCI) often lead to multiple neurological deficits as a result from the initial trauma and also the secondary damage that follows. Despite abundant preclinical data proposing anti-inflammatory therapies to minimize secondary injury and improve functional recovery, the field still lacks an effective neuroprotective treatment. Epigenetic proteins, such as bromodomain and extraterminal domain (BET) proteins, are emerging as new targets to regulate inflammation. More importantly, pharmacological inhibition of BET proteins suppresses pro-inflammatory gene transcription after SCI. In this study, we tested the therapeutic potential of inhibiting BET proteins after SCI with clinically relevant compounds, and investigated the role of the BET protein BRD4 in macrophages during progression of SCI pathology. Systemic inhibition of BET proteins with I-BET762 significantly reduced lesion size 8 weeks after a contusion injury in rats. However, we observed no histological or locomotor improvements after SCI when we deleted Brd4 in macrophages through the use of myeloid-specific Brd4 knockout mice or after macrophage-targeted pharmacological BET inhibition. Taken together, our data indicate that systemic I-BET762 treatment is neuroprotective, and the histopathological improvement observed is likely to be a result of effects on non-macrophage targets. Expanding our understanding on the role of BET proteins after SCI is necessary to identify novel therapeutic targets that can effectively promote repair after SCI.


Assuntos
Neuroproteção , Traumatismos da Medula Espinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ratos , Recuperação de Função Fisiológica/fisiologia , Roedores , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Pharmacol Res ; 178: 106149, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35240272

RESUMO

Neural tissue has high metabolic requirements. Following spinal cord injury (SCI), the damaged tissue suffers from a severe metabolic impairment, which aggravates axonal degeneration and neuronal loss. Impaired cellular energetic, tricarboxylic acid (TCA) cycle and oxidative phosphorylation metabolism in neuronal cells has been demonstrated to be a major cause of neural tissue death and regeneration failure following SCI. Therefore, rewiring the spinal cord cell metabolism may be an innovative therapeutic strategy for the treatment of SCI. In this study, we evaluated the therapeutic effect of the recovery of oxidative metabolism in a mouse model of severe contusive SCI. Oral administration of TCA cycle intermediates, co-factors, essential amino acids, and branched-chain amino acids was started 3 days post-injury and continued until the end of the experimental procedures. Metabolomic, immunohistological, and biochemical analyses were performed on the injured spinal cord sections. Administration of metabolic precursors enhanced spinal cord oxidative metabolism. In line with this metabolic shift, we observed the activation of the mTORC1 anabolic pathway, the increase in mitochondrial mass, and ROS defense which effectively prevented the injury-induced neural cell apoptosis in treated animals. Consistently, we found more choline acetyltransferase (ChAT)-expressing motor neurons and increased neurofilament-positive corticospinal axons in the spinal cord parenchyma of the treated mice. Interestingly, oral administration of the metabolic precursors increased the number of activated microglia expressing the CD206 marker suggestive of a pro-resolutive, M2-like phenotype. These molecular and histological modifications observed in treated animals ultimately led to a significant, although partial, improvement of the motor functions. Our data demonstrate that rewiring the cellular metabolism can represent an effective strategy to treat SCI.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Axônios/fisiologia , Metabolismo Energético , Camundongos , Microglia/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
13.
J Cell Mol Med ; 26(7): 1932-1942, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35257489

RESUMO

Numerous interventions have been explored in animal models using cells differentiated from human induced pluripotent stem cells (iPSCs) in the context of neural injury with some success. Our work seeks to transplant cells that are generated from hiPSCs into regionally specific spinal neural progenitor cells (sNPCs) utilizing a novel accelerated differentiation protocol designed for clinical translation. We chose a xenotransplantation model because our laboratory is focused on the behaviour of human cells in order to bring this potential therapy to translation. Cells were transplanted into adult immunodeficient rats after moderate contusion spinal cord injury (SCI). Twelve weeks later, cells derived from the transplanted sNPCs survived and differentiated into neurons and glia that filled the lesion cavity and produced a thoracic spinal cord transcriptional program in vivo. Furthermore, neurogenesis and ionic channel expression were promoted within the adjacent host spinal cord tissue. Transplanted cells displayed robust integration properties including synapse formation and myelination by host oligodendrocytes. Axons from transplanted hiPSC sNPC-derived cells extended both rostrally and caudally from the SCI transplant site, rostrally approximately 6 cm into supraspinal structures. Thus, iPSC-derived sNPCs may provide a patient-specific cell source for patients with SCI that could provide a relay system across the site of injury.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Traumatismos da Medula Espinal , Animais , Axônios/patologia , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Ratos , Recuperação de Função Fisiológica , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Sinapses/patologia
14.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 39(1): 10-18, 2022 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-35231961

RESUMO

Electric field stimulation (EFS) can effectively inhibit local Ca 2+ influx and secondary injury after spinal cord injury (SCI). However, after the EFS, the Ca 2+ in the injured spinal cord restarts and subsequent biochemical reactions are stimulated, which affect the long-term effect of EFS. Polyethylene glycol (PEG) is a hydrophilic polymer material that can promote cell membrane fusion and repair damaged cell membranes. This article aims to study the combined effects of EFS and PEG on the treatment of SCI. Sprague-Dawley (SD) rats were subjected to SCI and then divided into control group (no treatment, n = 10), EFS group (EFS for 30 min, n = 10), PEG group (covered with 50% PEG gelatin sponge for 5 min, n = 10) and combination group (combined treatment of EFS and PEG, n = 10). The measurement of motor evoked potential (MEP), the motor behavior score and spinal cord section fast blue staining were performed at different times after SCI. Eight weeks after the operation, the results showed that the latency difference of MEP, the amplitude difference of MEP and the ratio of cavity area of spinal cords in the combination group were significantly lower than those of the control group, EFS group and PEG group. The motor function score and the ratio of residual nerve tissue area in the spinal cords of the combination group were significantly higher than those in the control group, EFS group and PEG group. The results suggest that the combined treatment can reduce the pathological damage and promote the recovery of motor function in rats after SCI, and the therapeutic effects are significantly better than those of EFS and PEG alone.


Assuntos
Polietilenoglicóis , Traumatismos da Medula Espinal , Animais , Estimulação Elétrica , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Medula Espinal , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia
15.
Cell Mol Biol Lett ; 27(1): 27, 2022 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-35300585

RESUMO

BACKGROUND: After spinal cord injury (SCI), dysregulated or nonresolving inflammatory processes can severely disturb neuronal homeostasis and drive neurodegeneration. Although mesenchymal stromal cell (MSC)-based therapies have showed certain therapeutic efficacy, no MSC therapy has reached its full clinical goal. In this study, we examine interleukin-10 (IL10) genetically modified clinical-grade MSCs (IL10-MSCs) and evaluate their clinical safety, effectiveness, and therapeutic mechanism in a completely transected SCI mouse model. METHODS: We established stable IL10-overexpressing human umbilical-cord-derived MSCs through electric transduction and screened out clinical-grade IL10-MSCs according to the criteria of cell-based therapeutic products, which were applied to mice with completely transected SCI by repeated tail intravenous injections. Then we comprehensively investigated the motor function, histological structure, and nerve regeneration in SCI mice, and further explored the potential therapeutic mechanism after IL10-MSC treatment. RESULTS: IL10-MSC treatment markedly reinforced locomotor improvement, accompanied with decreased lesion volume, regeneration of axons, and preservation of neurons, compared with naïve unmodified MSCs. Further, IL10-MSC transplantation increased the ratio of microglia to infiltrated alternatively activated macrophages (M2), and reduced the ratio of classically activated macrophages (M1) at the injured spinal cord, meanwhile increasing the percentage of Treg and Th2 cells, and reducing the percentage of Th1 cells in the peripheral circulatory system. In addition, IL10-MSC administration could prevent apoptosis and promote neuron differentiation of neural stem cells (NSCs) under inflammatory conditions in vitro. CONCLUSIONS: IL10-MSCs exhibited a reliable safety profile and demonstrated promising therapeutic efficacy in SCI compared with naïve MSCs, providing solid support for future clinical application of genetically engineered MSCs.


Assuntos
Interleucina-10 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Animais , Interleucina-10/genética , Interleucina-10/uso terapêutico , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia
16.
Int J Mol Sci ; 23(6)2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35328642

RESUMO

Numerous intervention strategies have been developed to promote functional tissue repair following experimental spinal cord injury (SCI), including the bridging of lesion-induced cystic cavities with bioengineered scaffolds. Integration between such implanted scaffolds and the lesioned host spinal cord is critical for supporting regenerative growth, but only moderate-to-low degrees of success have been reported. Light and electron microscopy were employed to better characterise the fibroadhesive scarring process taking place after implantation of a longitudinally microstructured type-I collagen scaffold into unilateral mid-cervical resection injuries of the adult rat spinal cord. At long survival times (10 weeks post-surgery), sheets of tightly packed cells (of uniform morphology) could be seen lining the inner surface of the repaired dura mater of lesion-only control animals, as well as forming a barrier along the implant-host interface of the scaffold-implanted animals. The highly uniform ultrastructural features of these scarring cells and their anatomical continuity with the local, reactive spinal nerve roots strongly suggest their identity to be perineurial-like cells. This novel aspect of the cellular composition of reactive spinal cord tissue highlights the increasingly complex nature of fibroadhesive scarring involved in traumatic injury, and particularly in response to the implantation of bioengineered collagen scaffolds.


Assuntos
Colágeno Tipo I , Traumatismos da Medula Espinal , Animais , Cicatriz/patologia , Colágeno/química , Regeneração Nervosa/fisiologia , Ratos , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Tecidos Suporte/química
17.
J Neurotrauma ; 39(9-10): 735-749, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35171694

RESUMO

When the blood-spinal cord barrier (BSCB) is disrupted after a spinal cord injury (SCI), several pathophysiological cascades occur, including inflammation and apoptotic cell death of neurons and oligodendrocytes, resulting in permanent neurological deficits. Transient receptor potential melastatin 7 (TRPM7) is involved in the pathological processes in many neuronal diseases, including traumatic brain injury, amyotrophic lateral sclerosis, parkinsonism dementia, and Alzheimer's disease. Further, carvacrol (CAR), a TRPM7 inhibitor, is known to protect against SCI by reducing oxidative stress and inhibiting the endothelial nitric oxide synthase pathway. However, the functions of TRPM7 in the regulation of BSCB homeostasis after SCI have not been examined. Here, we demonstrated that TRPM7, a calcium-mediated non-selective divalent cation channel, plays a critical role after SCI in rats. Rats were contused at T9 and given CAR (50 mg/kg) intraperitoneally immediately and 12 h after SCI, and then given the same dose once a day for 7 days. TRPM7 was found to be up-regulated after SCI in both in vitro and in vivo studies, and it was expressed in blood vessels alongside neurons and oligodendrocytes. Additionally, CAR treatment suppressed BSCB disruption by inhibiting the loss of tight junction (TJ) proteins and preserved TJ integrity. CAR also reduced apoptotic cell death and improved functional recovery after SCI by preventing BSCB disruption caused by blood infiltration and inflammatory responses. Based on these findings, we propose that blocking the TRPM7 channel can inhibit the destruction of the BSCB and it is a potential target in therapeutic drug development for use in SCI.


Assuntos
Traumatismos da Medula Espinal , Canais de Cátion TRPM , Animais , Barreira Hematoencefálica/patologia , Cimenos , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Canais de Cátion TRPM/metabolismo
18.
Regen Med ; 17(4): 233-244, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35187979

RESUMO

The diagnosis and management of CNS injuries comprises a large portion of psychiatric practice. Many clinical and preclinical studies have demonstrated the benefit of treating CNS injuries using various regenerative techniques and materials such as stem cells, biomaterials and genetic modification. Therefore it is the goal of this review article to briefly summarize the pathogenesis of CNS injuries, including traumatic brain injuries, spinal cord injuries and cerebrovascular accidents. Next, we discuss the role of natural recovery and regeneration of the CNS, explore the relevance in clinical practice and discuss emerging and cutting-edge treatments and current barriers in the field of regenerative medicine.


When a person gets a cut on their skin, the human body can usually repair this injury on its own, allowing this tissue to return to normal function. In some cases, when the central nervous system (CNS) is damaged, the human body's regenerative capabilities are not sufficient to repair it. There are numerous treatments being explored in the field of regenerative medicine that have the potential to assist the human body in repairing the CNS after significant injury and to improve functionality. This paper explores how pharmacological and stem cell treatments, genetic modifications and implantable biomaterials can help repair damage to the CNS by replacing lost tissue and creating an environment that enhances healing.


Assuntos
Traumatismos da Medula Espinal , Materiais Biocompatíveis/uso terapêutico , Sistema Nervoso Central/patologia , Humanos , Regeneração Nervosa/fisiologia , Medicina Regenerativa , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia
19.
Neural Plast ; 2022: 2191011, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154311

RESUMO

The aim of this study was to investigate the effect of the P2Y2 receptor (P2Y2R) signaling pathway on neuronal regeneration and angiogenesis during spinal cord injury (SCI). The rats were randomly divided into 3 groups, including the sham+dimethyl sulfoxide (DMSO), SCI+DMSO, and SCI+P2Y2R groups. The SCI animal models were constructed. A locomotor rating scale was used for behavioral assessments. The apoptosis of spinal cord tissues was detected by TUNEL staining. The expression levels of P2Y2R, GFAP, nestin, Tuj1, and CD34 were detected by immunofluorescence staining, and the expression levels of TNF-α, IL-1ß, and IL-6 were detected by enzyme-linked immunosorbent assay. The locomotor score in the model group was significantly lower than the sham group. The expression of P2Y2R was increased after SCI. The expression levels of TNF-α, IL-1ß, and IL-6 were increased remarkably in the SCI model group compared with the sham group. The P2Y2R inhibitor relieved neuronal inflammation after SCI. Compared with the sham group, the apoptotic rate of spinal cord tissue cells in the model group was significantly increased. The P2Y2R inhibitor reduced the apoptosis of the spinal cord tissue. The expressions of CD34, Tuj1, and nestin in the model group were decreased, while the expressions of GFAP and P2Y2R were increased. The P2Y2R inhibitor reversed their expression levels. The P2Y2R inhibitor could alleviate SCI by relieving the neuronal inflammation, inhibiting the spinal cord tissue apoptosis, and promoting neuronal differentiation and vascular proliferation after SCI. P2Y2R may serve as a target for the treatment of SCI.


Assuntos
Regeneração Nervosa , Neurônios , Receptores Purinérgicos P2Y2 , Traumatismos da Medula Espinal , Medula Espinal , Animais , Modelos Animais de Doenças , Neovascularização Patológica , Regeneração Nervosa/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y2/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/irrigação sanguínea , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
20.
Bioengineered ; 13(3): 4844-4856, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35152833

RESUMO

The association between spinal cord injury (SCI) and bladder symptoms has been intensively described. Human umbilical cord mesenchymal stem cell (hUC-MSC) treatment is beneficial to the recovery of bladder function after SCI, but its mechanism is unclear. We established an SCI model, and prepared hUC-MSCs in advance, followed by verification using flow cytometry. The Basso, Beattie and Bresnahan (BBB) score and urodynamic index were employed to evaluate motor function and bladder functions, respectively. Hematoxylin-eosin staining, luxol fast blue staining, and Masson's trichrome staining were utilized to assess pathological changes. Real-time quantitative PCR and Western blot were used to determine the mRNA and protein expressions in bladder tissues. The immunophenotypes of the HUC-MSCs were CD90+ and CD105+, but CD34-, CD45- and HLA-DR-. Rats appeared severe motor dysfunction after SCI, but the BBB score was increased in hUC-MSCs after the second week. Pathologically, the improvement of the lesion area on the dorsal spinal cord, augmented anterior gray horn neuron cells of the spinal cord and lessened bladder tissue remodeling (fibrosis, collagen deposition) as well as modulated inflammation could be observed. Besides, SCI increased bladder weight, bladder capacity, urine volume and residual urine volume, and decreased urination efficiency. HUC-MSCs ameliorated SCI-induced pathological changes and bladder functions, the expressions of Collagen I, Collagen III, fibroblast growth factor 2 (FGF2), phospho-p38, transient receptor potential vanilloid 1, Toll-like receptor 4 and phospho-nuclear factor-kappa B (p-NF-κB). To sum up, HUC-MSCs contribute to the reconstruction of bladder function after SCI by repressing p38 MAPK/NF-κB pathway.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Animais , Colágeno/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Ratos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Cordão Umbilical/metabolismo , Cordão Umbilical/patologia , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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