RESUMEN
INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.
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Ratones Endogámicos C57BL , Polisacáridos , Recuperación de la Función , Remielinización , Traumatismos de la Médula Espinal , Animales , Polisacáridos/farmacología , Ratones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Remielinización/efectos de los fármacos , Remielinización/fisiología , Recuperación de la Función/efectos de los fármacos , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Femenino , Microambiente Celular/efectos de los fármacosRESUMEN
Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes of the brain. This process persists throughout life and is essential for recovery from neurodegeneration. To better understand the cellular checkpoints that occur during oligodendrogenesis, we determined the mitochondrial distribution and morphometrics across the oligodendrocyte lineage in mouse and human cerebral cortex. During oligodendrocyte generation, mitochondrial content expands concurrently with a change in subcellular partitioning towards the distal processes. These changes are followed by an abrupt loss of mitochondria in the oligodendrocyte processes and myelin, coinciding with sheath compaction. This reorganization and extensive expansion and depletion take 3 days. Oligodendrocyte mitochondria are stationary over days while OPC mitochondrial motility is modulated by animal arousal state within minutes. Aged OPCs also display decreased mitochondrial size, volume fraction, and motility. Thus, mitochondrial dynamics are linked to oligodendrocyte generation, dynamically modified by their local microenvironment, and altered in the aging brain.
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Mitocondrias , Vaina de Mielina , Oligodendroglía , Animales , Mitocondrias/metabolismo , Humanos , Oligodendroglía/metabolismo , Oligodendroglía/citología , Ratones , Vaina de Mielina/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/citología , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Ratones Endogámicos C57BL , Masculino , Dinámicas Mitocondriales , Diferenciación Celular , FemeninoRESUMEN
Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from a small cohort of post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating differentially expressed genes from three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified an association between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed an association with UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited an association with UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms.
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Oligodendroglía , Enfermedad de Parkinson , Transcriptoma , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Humanos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Transcriptoma/genética , Masculino , Femenino , Anciano , Células Precursoras de Oligodendrocitos/metabolismo , Estudios de Cohortes , Persona de Mediana EdadRESUMEN
Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs.
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Proliferación Celular , Histonas , Células Precursoras de Oligodendrocitos , Animales , Histonas/metabolismo , Histonas/genética , Acetilación , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/citología , Ratones , Oligodendroglía/metabolismo , Oligodendroglía/citología , Diferenciación Celular , Células Cultivadas , Ratones Endogámicos C57BLRESUMEN
Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition of the early ischemic lesion. Here we present a single cell resolution transcriptomics dataset of the brain´s acute response to infarction. Oligodendrocyte lineage cells and astrocytes range among the most transcriptionally perturbed populations and exhibit infarction- and subtype-specific molecular signatures. Specifically, we find infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and reactive astrocytes, exhibiting transcriptional commonalities in response to ischemic injury. OPCs and reactive astrocytes are involved in a shared immuno-glial cross talk with stroke-specific myeloid cells. Within the perilesional zone, osteopontin positive myeloid cells accumulate in close proximity to CD44+ proliferating OPCs and reactive astrocytes. In vitro, osteopontin increases the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition of acutely infarcted brain tissue.
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Astrocitos , Accidente Cerebrovascular Isquémico , Células Precursoras de Oligodendrocitos , Oligodendroglía , Análisis de la Célula Individual , Animales , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Masculino , Ratones , Análisis de la Célula Individual/métodos , Oligodendroglía/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Astrocitos/metabolismo , Neuroglía/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Transcriptoma , Análisis de Secuencia de ARN/métodos , Ratones Endogámicos C57BL , Encéfalo/metabolismo , Encéfalo/patología , Ratas , Proliferación Celular , Movimiento Celular/genética , Células Mieloides/metabolismo , Modelos Animales de Enfermedad , Núcleo Celular/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologíaRESUMEN
The diversity of oligodendrocyte precursor cells (OPCs) is not well understood and is actively discussed in the field. A new study in PLOS Biology describes a novel marker for an OPC subpopulation that controls oligodendrogenesis and myelination.
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Diferenciación Celular , Oligodendroglía , Oligodendroglía/fisiología , Oligodendroglía/metabolismo , Oligodendroglía/citología , Animales , Humanos , Vaina de Mielina/metabolismo , Vaina de Mielina/fisiología , Células Precursoras de Oligodendrocitos/fisiología , Células Precursoras de Oligodendrocitos/citología , Células Precursoras de Oligodendrocitos/metabolismo , Biomarcadores/metabolismoRESUMEN
BACKGROUND: Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY: In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION: We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.
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Inflamación , Esclerosis Múltiple , Células Precursoras de Oligodendrocitos , Remielinización , Humanos , Remielinización/fisiología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patología , Animales , Inflamación/inmunología , Diferenciación Celular/fisiología , Vaina de Mielina , OligodendroglíaRESUMEN
Cell therapy for the treatment of demyelinating diseases such as multiple sclerosis is hampered by poor survival of donor oligodendrocyte cell preparations, resulting in limited therapeutic outcomes. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection. Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of primary human oligodendrocyte progenitor cells (hOPCs) to the brain of a shiverer/rag2 mouse, a model of congenital hypomyelinating disease. The STHs enabled immobilization of prosurvival signals, including a recombinantly designed bidomain peptide and platelet-derived growth factor. Notably, STHs reduced the death rate of hOPCs significantly, promoted the production of myelinating oligodendrocytes, and enhanced myelination of the mouse brain 12 weeks post-implantation. Our results demonstrate the potential of STHs loaded with biological cues to improve cell therapies for the treatment of devastating myelopathies.
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Supervivencia Celular , Hidrogeles , Células Precursoras de Oligodendrocitos , Remielinización , Animales , Hidrogeles/química , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/citología , Ratones , Humanos , Sistema Nervioso Central/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/citología , Vaina de Mielina/metabolismo , Modelos Animales de EnfermedadRESUMEN
Introduction: Glioma, a prevalent and deadly brain tumor, is marked by significant cellular heterogeneity and metabolic alterations. However, the comprehensive cell-of-origin and metabolic landscape in high-grade (Glioblastoma Multiforme, WHO grade IV) and low-grade (Oligoastrocytoma, WHO grade II) gliomas remains elusive. Methods: In this study, we undertook single-cell transcriptome sequencing of these glioma grades to elucidate their cellular and metabolic distinctions. Following the identification of cell types, we compared metabolic pathway activities and gene expressions between high-grade and low-grade gliomas. Results: Notably, astrocytes and oligodendrocyte progenitor cells (OPCs) exhibited the most substantial differences in both metabolic pathways and gene expression, indicative of their distinct origins. The comprehensive analysis identified the most altered metabolic pathways (MCPs) and genes across all cell types, which were further validated against TCGA and CGGA datasets for clinical relevance. Discussion: Crucially, the metabolic enzyme phosphodiesterase 8B (PDE8B) was found to be exclusively expressed and progressively downregulated in astrocytes and OPCs in higher-grade gliomas. This decreased expression identifies PDE8B as a metabolism-related oncogene in IDH-mutant glioma, marking its dual role as both a protective marker for glioma grading and prognosis and as a facilitator in glioma progression.
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3',5'-AMP Cíclico Fosfodiesterasas , Neoplasias Encefálicas , Glioma , Mutación , Humanos , Astrocitos/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Regulación hacia Abajo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/patología , Isocitrato Deshidrogenasa/genética , Clasificación del Tumor , Células Precursoras de Oligodendrocitos/metabolismo , Oncogenes , Análisis de la Célula Individual , Transcriptoma , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismoRESUMEN
Oligodendrocyte precursor cells (OPCs) have long been regarded as progenitors of oligodendrocytes, yet recent advances have illuminated their multifaceted nature including their emerging immune functions. This review seeks to shed light on the immune functions exhibited by OPCs, spanning from phagocytosis to immune modulation and direct engagement with immune cells across various pathological scenarios. Comprehensive understanding of the immune functions of OPCs alongside their other roles will pave the way for targeted therapies in neurological disorders.
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Células Precursoras de Oligodendrocitos , Humanos , Células Precursoras de Oligodendrocitos/inmunología , Animales , Fagocitosis/inmunología , Oligodendroglía/inmunología , Diferenciación Celular/inmunología , InmunomodulaciónRESUMEN
The abnormal growth of oligodendrocyte precursor cells (OPCs) significantly contributes to the progression of glioblastoma tumors. Hence, molecules that block OPC growth may be of therapeutic importance in treating gliomas. 2-Methoxyestradiol (2ME), an endogenous tubulin-interacting metabolite of estradiol, is effective against multiple proliferative disorders. Based on its anti-carcinogenic and anti-angiogenic actions, it is undergoing phase II clinical trials. We hypothesize that 2ME may prevent glioma growth by targeting OPC growth. Here, we tested this hypothesis by assessing the impact of 2ME on the growth of an OPC line, "Oli-neu", and dissected the underlying mechanism(s). Treatment with 2ME inhibited OPC growth in a concentration-dependent manner, accompanied by significant upregulation in the expression of p21 and p27, which are negative cell-cycle regulators. Moreover, treatment with 2ME altered OPC morphology from multi-arm processes to rounded cells. At concentrations of 1uM and greater, 2ME induced apoptosis, with increased expressions of caspase 3, PARP, and caspase-7 fragments, externalized phosphatidylserine staining/APOPercentage, and increased mitochondrial activity. Flow cytometry and microscopic analysis demonstrated that 2ME triggers endoreduplication in a concentration-dependent fashion. Importantly, 2ME induced cyclin E, JNK1/2, and p53 expression, as well as OPC fusion, which are key mechanisms driving endoreduplication and whole-genome duplication. Importantly, the inhibition of p53 with pifithrin-α rescued 2ME-induced endoreduplication. The pro-apoptotic and endoreduplication actions of 2ME were accompanied by the upregulation of survivin, cyclin A, Cyclin B, Cyclin D2, and ppRB. Similar growth inhibitory, apoptotic, and endoreduplication effects of 2ME were observed in CG4 cells. Taken together, our findings provide evidence that 2ME not only inhibits OPC growth and triggers apoptosis, but also activates OPCs into survival (fight or flight) mode, leading to endoreduplication. This inherent survival characteristic of OPCs may, in part, be responsible for drug resistance in gliomas, as observed for many tubulin-interacting drugs. Importantly, the fate of OPCs after 2ME treatment may depend on the cell-cycle status of individual cells. Combining tubulin-interfering molecules with drugs such as pifithrin-α that inhibit endoreduplication may help inhibit OPC/glioma growth and limit drug resistance.
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2-Metoxiestradiol , Apoptosis , Proteína p53 Supresora de Tumor , 2-Metoxiestradiol/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Animales , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Humanos , Estradiol/farmacología , Estradiol/análogos & derivados , Oligodendroglía/metabolismo , Oligodendroglía/efectos de los fármacos , Antimitóticos/farmacología , Línea CelularRESUMEN
Oligodendrocyte precursor cells (OPCs) are a class of glial cells that uniformly tiles the entire central nervous system (CNS). They play several key functions across the brain including the generation of oligodendrocytes and the control of myelination. Whether the functional diversity of OPCs is the result of genetically defined subpopulations or of their regulation by external factors has not been definitely established. We discovered that a subpopulation of OPCs found across the brain is defined by the expression of C1ql1, a gene previously described for its synaptic function in neurons. This subpopulation starts to appear during the first postnatal week in the mouse cortex. Ablation of C1ql1-expressing OPCs in the mouse leads to a massive lack of oligodendrocytes and myelination in many brain regions. This deficit cannot be rescued, even though some OPCs escape Sox10-driven ablation and end up partially compensating the OPC loss in the adult. Therefore, C1ql1 is a molecular marker of a functionally non-redundant subpopulation of OPCs, which controls the generation of myelinating oligodendrocytes.
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Vaina de Mielina , Células Precursoras de Oligodendrocitos , Oligodendroglía , Animales , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/citología , Oligodendroglía/metabolismo , Oligodendroglía/citología , Vaina de Mielina/metabolismo , Ratones , Diferenciación Celular/genética , Encéfalo/metabolismo , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión GénicaRESUMEN
Oligodendrocyte precursor cells (OPCs) comprise 5-8â¯% of the adult glial cell population and stand out as the most proliferative cell type in the central nervous system (CNS). OPCs are responsible for generating oligodendrocytes (OLs), the myelinating cells of the CNS. However, OPC functions decline as we age, resulting in impaired differentiation and inadequate remyelination. This review explores the cellular and molecular changes associated with OPC aging, and their impact on OPC differentiation and functionality. Furthermore, it examines the impact of OPC aging within the context of multiple sclerosis and Alzheimer's disease, both neurodegenerative conditions wherein aged OPCs exacerbate disease progression by impeding remyelination. Moreover, various pharmacological interventions targeting pathways related to senescence and differentiation are discussed as potential strategies to rejuvenate aged OPCs. Enhancing our understanding of OPC aging mechanisms holds promise for developing new therapies to improve remyelination and repair in age-related neurodegenerative disorders.
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Encéfalo , Diferenciación Celular , Senescencia Celular , Células Precursoras de Oligodendrocitos , Humanos , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/fisiología , Senescencia Celular/fisiología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Diferenciación Celular/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Envejecimiento/fisiología , Envejecimiento/metabolismo , Envejecimiento/patología , Oligodendroglía/metabolismo , Remielinización/fisiologíaRESUMEN
Within the adult mouse subventricular zone (SVZ), neural stem cells (NSCs) produce neuroblasts and oligodendrocyte precursor cells (OPCs). T3, the active thyroid hormone, influences renewal and commitment of SVZ progenitors. However, how regulators of T3 availability affect these processes is less understood. Using Mct8/Dio2 knockout mice, we investigated the role of MCT8, a TH transporter, and DIO2, the T3-generating enzyme, in regulating adult SVZ-neurogliogenesis. Single-cell RNA-Seq revealed Mct8 expression in various SVZ cell types in WT mice, while Dio2 was enriched in neurons, astrocytes, and quiescent NSCs. The absence of both regulators in the knockout model dysregulated gene expression, increased the neuroblast/OPC ratio and hindered OPC differentiation. Immunostainings demonstrated compromised neuroblast migration reducing their supply to the olfactory bulbs, impairing interneuron differentiation and odor discrimination. These findings underscore the pivotal roles of MCT8 and DIO2 in neuro- and oligodendrogenesis, offering targets for therapeutic avenues in neurodegenerative and demyelinating diseases.
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Ventrículos Laterales , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos , Células-Madre Neurales , Neurogénesis , Animales , Neurogénesis/fisiología , Ratones , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Células-Madre Neurales/metabolismo , Ventrículos Laterales/metabolismo , Yodotironina Deyodinasa Tipo II , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Diferenciación Celular/fisiología , Simportadores/genética , Simportadores/metabolismo , Bulbo Olfatorio/metabolismo , Ratones Endogámicos C57BL , Células Precursoras de Oligodendrocitos/metabolismoRESUMEN
Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.
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Diferenciación Celular , Macrófagos , Células Precursoras de Oligodendrocitos , Remielinización , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Macrófagos/metabolismo , Remielinización/fisiología , Diferenciación Celular/fisiología , Células Precursoras de Oligodendrocitos/metabolismo , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Recuperación de la Función/fisiología , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Transgénicos , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Oligodendroglía/metabolismoRESUMEN
Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte-neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.
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Astrocitos , Traumatismos de la Médula Espinal , Accidente Cerebrovascular , Cicatrización de Heridas , Animales , Astrocitos/metabolismo , Astrocitos/patología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Ratones , Masculino , Cicatrización de Heridas/fisiología , Cicatrización de Heridas/genética , Femenino , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/genética , Ratones Endogámicos C57BL , Reprogramación Celular/fisiología , Células Precursoras de Oligodendrocitos/metabolismo , Proliferación Celular/fisiologíaRESUMEN
The kappa opioid receptor has been identified as a promising therapeutic target for promoting remyelination. In the current study, we evaluated the ability of nalfurafine to promote oligodendrocyte progenitor cell (OPC) differentiation and myelination in vitro, and its efficacy in an extended, cuprizone-induced demyelination model. Primary mouse (C57BL/6J) OPC-containing cultures were treated with nalfurafine (0.6-200 nM), clemastine (0.01-100 µM), T3 (30 ng/mL), or vehicle for 5 days. Using immunocytochemistry and confocal microscopy, we found that nalfurafine treatment increased OPC differentiation, oligodendrocyte (OL) morphological complexity, and myelination of nanofibers in vitro. Adult male mice (C57BL/6J) were given a diet containing 0.2% cuprizone and administered rapamycin (10 mg/kg) once daily for 12 weeks followed by 6 weeks of treatment with nalfurafine (0.01 or 0.1 mg/kg), clemastine (10 mg/kg), or vehicle. We quantified the number of OLs using immunofluorescence, gross myelination using black gold staining, and myelin thickness using electron microscopy. Cuprizone + rapamycin treatment produced extensive demyelination and was accompanied by a loss of mature OLs, which was partially reversed by therapeutic administration of nalfurafine. We also assessed these mice for functional behavioral changes in open-field, horizontal bar, and mouse motor skill sequence tests (complex wheel running). Cuprizone + rapamycin treatment resulted in hyperlocomotion, poorer horizontal bar scores, and less distance traveled on the running wheels. Partial recovery was observed on both the horizontal bar and complex running wheel tests over time, which was facilitated by nalfurafine treatment. Taken together, these data highlight the potential of nalfurafine as a remyelination-promoting therapeutic.
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Cuprizona , Enfermedades Desmielinizantes , Ratones Endogámicos C57BL , Morfinanos , Vaina de Mielina , Sirolimus , Compuestos de Espiro , Animales , Morfinanos/farmacología , Masculino , Compuestos de Espiro/farmacología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/tratamiento farmacológico , Ratones , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Sirolimus/farmacología , Cuprizona/toxicidad , Células Cultivadas , Modelos Animales de Enfermedad , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Células Precursoras de Oligodendrocitos/metabolismo , Diferenciación Celular/efectos de los fármacosRESUMEN
Oligodendrocyte progenitor cells (OPCs) represent a subtype of glia, giving rise to oligodendrocytes, the myelin-forming cells in the central nervous system (CNS). While OPCs are highly proliferative during development, they become relatively quiescent during adulthood, when their fate is strictly influenced by the extracellular context. In traumatic injuries and chronic neurodegenerative conditions, including those of autoimmune origin, oligodendrocytes undergo apoptosis, and demyelination starts. Adult OPCs become immediately activated; they migrate at the lesion site and proliferate to replenish the damaged area, but their efficiency is hampered by the presence of a glial scar-a barrier mainly formed by reactive astrocytes, microglia and the deposition of inhibitory extracellular matrix components. If, on the one hand, a glial scar limits the lesion spreading, it also blocks tissue regeneration. Therapeutic strategies aimed at reducing astrocyte or microglia activation and shifting them toward a neuroprotective phenotype have been proposed, whereas the role of OPCs has been largely overlooked. In this review, we have considered the glial scar from the perspective of OPCs, analysing their behaviour when lesions originate and exploring the potential therapies aimed at sustaining OPCs to efficiently differentiate and promote remyelination.
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Cicatriz , Neuroglía , Células Precursoras de Oligodendrocitos , Remielinización , Humanos , Animales , Células Precursoras de Oligodendrocitos/metabolismo , Cicatriz/patología , Neuroglía/metabolismo , Neuroglía/patología , Oligodendroglía/metabolismo , Oligodendroglía/citología , Vaina de Mielina/metabolismo , Diferenciación CelularRESUMEN
Neonatal hypoxia-ischemia (HI) results in behavioral deficits, characterized by neuronal injury and retarded myelin formation. To date, limited treatment methods are available to prevent or alleviate neurologic sequelae of HI. Intermittent theta-burst stimulation (iTBS), a non-invasive therapeutic procedure, is considered a promising therapeutic tool for treating some neurocognitive disorders and neuropsychiatric diseases. Hence, this study aims to investigate whether iTBS can prevent the negative behavioral manifestations of HI and explore the mechanisms for associations. We exposed postnatal day 10 Sprague-Dawley male and female rats to 2 h of hypoxia (6% O2) following right common carotid artery ligation, resulting in oligodendrocyte (OL) dysfunction, including reduced proliferation and differentiation of oligodendrocyte precursor cells (OPCs), decreased OL survival, and compromised myelin in the corpus callosum (CC) and hippocampal dentate gyrus (DG). These alterations were concomitant with cognitive dysfunction and depression-like behaviors. Crucially, early iTBS treatment (15 G, 190 s, seven days, initiated one day post-HI) significantly alleviated HI-caused myelin damage and mitigated the neurologic sequelae both in male and female rats. However, the late iTBS treatment (initiated 18 days after HI insult) could not significantly impact these behavioral deficits. In summary, our findings support that early iTBS treatment may be a promising strategy to improve HI-induced neurologic disability. The underlying mechanisms of iTBS treatment are associated with promoting the differentiation of OPCs and alleviating myelin damage.
Asunto(s)
Animales Recién Nacidos , Hipoxia-Isquemia Encefálica , Vaina de Mielina , Ratas Sprague-Dawley , Animales , Masculino , Femenino , Ratas , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/patología , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Estimulación Magnética Transcraneal/métodos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Células Precursoras de OligodendrocitosRESUMEN
Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-CreERT2 (control), Smofl/fl/NG2-CreERT2 (loss of function), and SmoM2/NG2-CreERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.