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1.
Neuron ; 105(2): 293-309.e5, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31901304

RESUMO

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N6-methyladenosine (m6A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m6A modification on numerous transcripts. In vivo conditional inactivation of an essential m6A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination.


Assuntos
Adenosina/análogos & derivados , Diferenciação Celular/fisiologia , Metiltransferases/fisiologia , Bainha de Mielina/fisiologia , Oligodendroglia/citologia , Oligodendroglia/fisiologia , RNA Mensageiro/metabolismo , Adenosina/metabolismo , Animais , Moléculas de Adesão Celular/metabolismo , Contagem de Células , Linhagem da Célula , Células Cultivadas , Feminino , Masculino , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/metabolismo , Células Precursoras de Oligodendrócitos/fisiologia
2.
Adv Exp Med Biol ; 1190: 3-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760634

RESUMO

Increasing studies have demonstrated multiple signaling molecules responsible for oligodendrocytes and Schwann cells development such as migration, differentiation, myelination, and axo-glial interaction. However, complicated roles in these events are still poorly understood. This chapter focuses on well established intracellular signaling transduction and recent topics that control myelination and are elucidated from accumulating evidences. The underlying molecular mechanisms, which involved in membrane trafficking through small GTPase Arf6 and its activator cytohesins, demonstrate the crosstalk between well established intracellular signaling transduction and a new finding signaling pathway in glial cells links to physiological phenotype and essential role in peripheral nerve system (PNS). Since Arf family proteins affect the expression levels of myelin protein zero (MPZ) and Krox20, which is a transcription factor regulatory factor in early developmental stages of Schwann cells, Arf proteins likely to be key regulator for Schwann cells development. Herein, we discuss how intracellular signaling transductions in Schwann cells associate with myelination in CNS and PNS.


Assuntos
Remielinização , Células de Schwann/fisiologia , Transdução de Sinais , Humanos , Bainha de Mielina/fisiologia , Neuroglia/fisiologia , Oligodendroglia/fisiologia
3.
Adv Exp Med Biol ; 1190: 33-42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760636

RESUMO

Myelination and remyelination in the central nervous system (CNS) are essential for rapid conduction of action potentials and for appropriate neuronal communications supporting higher brain functions. Myelination is dependent on developmental stage and is controlled by neuronal axons-oligodendrocyte (OL) signaling. Numerous studies of the initial myelination and remyelination stages in the CNS have demonstrated several key cytoskeletal signals in axons and OLs. In this review, we focus on cytoskeletal signal-regulated OL myelination and remyelination, with particular attention to neuronal Notch proteins, bidirectional Eph/ephrin signaling, OL integrin and cadherin superfamily proteins, OL actin rearrangement, and OL tyrosine kinase Fyn substrate proteins during the initial myelination and remyelination stages in the CNS.


Assuntos
Citoesqueleto/fisiologia , Oligodendroglia/fisiologia , Remielinização , Transdução de Sinais , Sistema Nervoso Central/fisiologia , Efrinas/fisiologia , Humanos , Bainha de Mielina/fisiologia , Receptores Notch/fisiologia
4.
Adv Exp Med Biol ; 1190: 43-51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760637

RESUMO

Oligodendrocyte form myelin around the axons to regulate the conduction velocity. Myelinated axons are composed of white matter to act as cables to connect distinct brain regions. Recent human MRI studies showed that the signal from white matter change in the people with special skills such as taxi driver, piano player, and juggling. The change of the white matter suggested that (1) The plasticity of myelination depends on neuronal activity (activity-dependent myelination) and (2) White matter plasticity is essential for brain functions. In this session, we discussed that how the un-electrical components, oligodendrocytes, and its precursor cells receive the signal from electrically active neurons and differentiate, proliferate, and myelinate the axons to modulate the activity of neuronal circuits, ultimately affect on their behaviors. In this review, we highlight the physiological functions of oligodendrocyte and their neuronal activity-dependent functions and thus show new insight for their contribution to brain functions.


Assuntos
Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Substância Branca/fisiologia , Axônios/fisiologia , Humanos , Neurônios/fisiologia
5.
Adv Exp Med Biol ; 1190: 53-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760638

RESUMO

While oligodendrocytes have been thought to be homogenous, a number of reports have indicated evidences of the heterogeneity of oligodendrocytes and their precursor cells, OPCs. Almost a century ago, Del Río Hortega found three and four types of oligodendrocytes with regions where they exist and their morphologies, respectively. Interfascicular oligodendrocytes are one of the three regional dependent types and are the most typical oligodendendroglial cells that myelinate axonal fibers in the white matter tracts. In the other two, perineuronal oligodendrocyes function as reserve cells for remyelination and regulate neuronal excitability, whereas perivascular oligodendrocytes may play a role in metabolic support of axons. Among the four morphological categories, type I and II oligodendrocytes form many myelin sheaths on small-diameter axons and specific signal is required for the myelination of small-diameter axons. Type III and IV oligodendrocytes myelinate a few number of axons/or one axon, whose diameters are large. A recent comprehensive gene expression analysis with single-cell RNA sequencing identifies six different populations in mature oligodendrocytes and only one population in OPCs. However, OPCs are not uniformed developmentally and regionally. Further, the capacity of OPC differentiation depends on the environments and conditions of the tissues. Taken together, oligodendrocytes and OPCs are diverse as the other cell types in the CNS. The orchestration of these cells with their specialized functions is critical for proper functioning of the CNS.


Assuntos
Sistema Nervoso Central/fisiologia , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Axônios/fisiologia , Diferenciação Celular , Humanos , Neurônios/fisiologia , Substância Branca/fisiologia
6.
Adv Exp Med Biol ; 1190: 123-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760642

RESUMO

Oligodendrocytes enable saltatory conduction by forming a myelin sheath around axons, dramatically boosts action potential conduction velocity. In addition to this canonical function of oligodendrocytes, it is now known that oligodendrocytes can respond to neuronal activity and regulate axonal conduction. Importantly, white matter plasticity, including adaptive responses by oligodendrocytes, has been shown to be involved in learning and memory. In this chapter, the role of oligodendrocytes in axonal conduction and axonal excitability will be reviewed. Focus will be paid to the mechanisms through which oligodendrocytes, including perineuronal oligodendrocytes, facilitate and suppress axonal conduction.


Assuntos
Axônios/fisiologia , Condução Nervosa , Oligodendroglia/fisiologia , Humanos , Bainha de Mielina/fisiologia , Substância Branca/fisiologia
7.
Adv Exp Med Biol ; 1190: 165-179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760644

RESUMO

Myelin is heavily enriched in lipids (comprising approximately 70% of its dry weight), and the amount of cholesterol and glycolipids is higher than in any other cell membrane. Galactocerebroside (GalC) and its sulfated form, sulfatide, comprise the major glycolipid components of myelin. Their functional significance has been extensively studied using membrane models, cell culture, and in vivo experiments in which either GalC/sulfatide or sulfatide is deficient. From these studies, GalC and sulfatide have been distinctly localized within oligodendrocytes and their specific function in myelin has been elucidated. Here, the function of sulfatide in axo-glial interactions in myelin-forming cells as well as within myelin and its potential mechanisms of action are discussed.


Assuntos
Axônios/fisiologia , Bainha de Mielina/química , Neuroglia/fisiologia , Sulfoglicoesfingolipídeos/química , Humanos , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia
8.
Adv Exp Med Biol ; 1190: 265-279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760650

RESUMO

Given recent progress in our understanding of oligodendrocyte biology, significant attention has been directed toward cell therapy for myelin repair and remyelination. This trend has been reinforced by findings about the importance of white matter lesions in a variety of central nervous system (CNS) diseases, including demyelinating diseases as well as brain or spinal cord trauma and degenerative disorders such as Alzheimer's disease. Remyelination strategies include the implementation of myelin forming cells and the surrounding conditions and pathological disease context. Successful remyelination requires proper number of cells at the required location and subsequent maturation. Those processes involve variety of molecules, related to oligodendrocyte development or inflammation in the lesion. Understanding and manipulation of the functions of those molecules may improve the outcome of the cell therapies toward remyelination. Furthermore, the development of monitoring method for myelination is also anticipated to evaluate the effects of therapeutic interventions.


Assuntos
Doenças Desmielinizantes/terapia , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Remielinização , Traumatismos da Medula Espinal/terapia , Humanos , Bainha de Mielina/patologia , Oligodendroglia/patologia
9.
Adv Exp Med Biol ; 1175: 117-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583586

RESUMO

Oligodendrocytes are the myelinating cells of the CNS, producing the insulating myelin sheath that facilitates rapid electrical conduction of axonal action potentials. Oligodendrocytes arise from oligodendrocyte progenitor cells (OPCs) under the control of multiple factors, including neurotransmitters and other neuron-derived factors. A significant population of OPCs persists in the adult CNS, where they are often referred to as NG2-glia, because they are identified by their expression of the NG2 chondroitin sulphate proteoglycan (CSPG4). In the adult brain, the primary function of NG2-glia is the life-long generation of oligodendrocytes to replace myelin lost through natural 'wear and tear' and pathology, as well as to provide new oligodendrocytes to myelinate new connections formed in response to new life experiences. NG2-glia contact synapses and respond to neurotransmitters and potassium released during neuronal transmission; to this end, NG2-glia (OPCs) express multiple neurotransmitter receptors and ion channels, with prominent roles being identified for glutamatergic signalling and potassium channels in oligodendrocyte differentiation. Myelinating oligodendrocytes also express a wide range of neurotransmitter receptors and ion channels, together with transporters and gap junctions; together, these have critical functions in cellular ion and water homeostasis, as well as metabolism, which is essential for maintaining myelin and axon integrity. An overriding theme is that oligodendrocyte function and myelination is not only essential for rapid axonal conduction, but is essential for learning and the long-term integrity of axons and neurones. Hence, myelination underpins cognitive function and the massive computing power of the human brain and myelin loss has devastating effects on CNS function. This chapter focuses on normal oligodendrocyte physiology.


Assuntos
Bainha de Mielina , Oligodendroglia/fisiologia , Axônios , Humanos , Células-Tronco Neurais/citologia , Neurônios
10.
PLoS Biol ; 17(6): e3000330, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31226122

RESUMO

The repair of white matter damage is of paramount importance for functional recovery after brain injuries. Here, we report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 d after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific peroxisome proliferator-activated receptor gamma (PPARγ) knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the central nervous system (CNS), which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.


Assuntos
Interleucina-4/metabolismo , Oligodendroglia/metabolismo , PPAR gama/metabolismo , Animais , Lesões Encefálicas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Diferenciação Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Interleucina-4/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa , Neurogênese , Oligodendroglia/fisiologia , PPAR gama/fisiologia , Recuperação de Função Fisiológica , Remielinização/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral , Substância Branca
11.
Res Vet Sci ; 125: 71-81, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152923

RESUMO

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system that destroys oligodendrocytes. This work aims to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture. The study concluded that treatment using laser activated stem cells holds a promising therapeutic option for treatment of MS in a canine model.


Assuntos
Adipócitos/fisiologia , Tecido Adiposo/citologia , Células-Tronco Mesenquimais/fisiologia , Esclerose Múltipla/terapia , Oligodendroglia/fisiologia , Adipócitos/efeitos da radiação , Tecido Adiposo/efeitos da radiação , Animais , Diferenciação Celular , Modelos Animais de Doenças , Cães , Imuno-Histoquímica/veterinária , Lasers , Imagem por Ressonância Magnética/veterinária , Células-Tronco Mesenquimais/efeitos da radiação , Proteína Básica da Mielina , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/efeitos da radiação , Distribuição Aleatória , Medula Espinal/patologia , Medula Espinal/ultraestrutura
12.
Glia ; 67(9): 1745-1759, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31162728

RESUMO

Deficient myelination, the spiral wrapping of highly specialized membrane around axons, causes severe neurological disorders. Maturation of oligodendrocyte progenitor cells (OPC) to myelinating oligodendrocytes (OL), the sole providers of central nervous system (CNS) myelin, is tightly regulated and involves extensive morphological changes. Here, we present evidence that autophagy, the targeted isolation of cytoplasm and organelles by the double-membrane autophagosome for lysosomal degradation, is essential for OPC/OL differentiation, survival, and proper myelin development. A marked increase in autophagic activity coincides with OL differentiation, with OL processes having the greatest increase in autophagic flux. Multiple lines of evidence indicate that autophagosomes form in developing myelin sheathes before trafficking from myelin to the OL soma. Mice with conditional OPC/OL-specific deletion of the essential autophagy gene Atg5 beginning on postnatal Day 5 develop a rapid tremor and die around postnatal Day 12. Further analysis revealed apoptotic death of OPCs, reduced differentiation, and reduced myelination. Surviving Atg5-/- OLs failed to produce proper myelin structure. In vitro, pharmacological inhibition of autophagy in OPC/dorsal root ganglion (DRG) co-cultures blocked myelination, producing OLs surrounded by many short processes. Conversely, autophagy stimulation enhanced myelination. These results implicate autophagy as a key regulator of OPC survival, maturation, and proper myelination. Autophagy may provide an attractive target to promote both OL survival and subsequent myelin repair after injury.


Assuntos
Autofagia/fisiologia , Sobrevivência Celular/fisiologia , Neurogênese/fisiologia , Células Precursoras de Oligodendrócitos/fisiologia , Oligodendroglia/fisiologia , Animais , Proteína 5 Relacionada à Autofagia/deficiência , Proteína 5 Relacionada à Autofagia/genética , Células Cultivadas , Córtex Cerebral/fisiologia , Técnicas de Cocultura , Feminino , Gânglios Espinais/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos Sprague-Dawley
13.
Glia ; 67(8): 1510-1525, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31038798

RESUMO

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Mesenquimais/fisiologia , Oligodendroglia/fisiologia , Remielinização/fisiologia , Animais , Células Cultivadas , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos
14.
Glia ; 67(8): 1571-1597, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31033049

RESUMO

Astrocytes are critical for the development and function of the central nervous system. In developing brains, immature astrocytes undergo morphological, molecular, cellular, and functional changes as they mature. Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied, little is known about the cellular and molecular mechanisms that control astrocyte maturation. Here, we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation. Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo. Using this system, we found that astrocyte-to-astrocyte contact strongly promotes astrocyte maturation. In addition, secreted signals from microglia, oligodendrocyte precursor cells, or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation. To identify molecular mechanisms underlying astrocyte maturation, we treated maturing astrocytes with molecules that affect the function of tumor-associated genes. We found that a positive feedback loop of heparin-binding epidermal growth factor-like growth factor (HBEGF) and epidermal growth factor receptor (EGFR) signaling regulates astrocytes maturation. Furthermore, HBEGF, EGFR, and tumor protein 53 (TP53) affect the expression of genes important for cilium development, the circadian clock, and synapse function. These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.


Assuntos
Astrócitos/fisiologia , Comunicação Celular/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Animais , Astrócitos/ultraestrutura , Células Cultivadas , Células Endoteliais/fisiologia , Receptores ErbB/genética , Retroalimentação Fisiológica , Genes Neoplásicos/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Microglia/fisiologia , Oligodendroglia/fisiologia , Ratos , Proteína Supressora de Tumor p53/genética
15.
Elife ; 82019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30998186

RESUMO

Neuron-glia communication contributes to the fine-tuning of synaptic functions. Oligodendrocytes near synapses detect and respond to neuronal activity, but their role in synapse development and plasticity remains largely unexplored. We show that oligodendrocytes modulate neurotransmitter release at presynaptic terminals through secretion of brain-derived neurotrophic factor (BDNF). Oligodendrocyte-derived BDNF functions via presynaptic tropomyosin receptor kinase B (TrkB) to ensure fast, reliable neurotransmitter release and auditory transmission in the developing brain. In auditory brainstem slices from Bdnf+/- mice, reduction in endogenous BDNF significantly decreased vesicular glutamate release by reducing the readily releasable pool of glutamate vesicles, without altering presynaptic Ca2+ channel activation or release probability. Using conditional knockout mice, cell-specific ablation of BDNF in oligodendrocytes largely recapitulated this effect, which was recovered by BDNF or TrkB agonist application. This study highlights a novel function for oligodendrocytes in synaptic transmission and their potential role in the activity-dependent refinement of presynaptic properties.


Assuntos
Tronco Encefálico/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Oligodendroglia/fisiologia , Terminações Pré-Sinápticas/fisiologia , Transmissão Sináptica , Animais , Técnicas de Inativação de Genes , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas Tirosina Quinases/metabolismo
16.
Glia ; 67(8): 1462-1477, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30989733

RESUMO

Neuronal activity is a potent extrinsic regulator of oligodendrocyte generation and central nervous system myelination. Clinically, repetitive transcranial magnetic stimulation (rTMS) is delivered to noninvasively modulate neuronal activity; however, the ability of rTMS to facilitate adaptive myelination has not been explored. By performing cre-lox lineage tracing, to follow the fate of oligodendrocyte progenitor cells in the adult mouse brain, we determined that low intensity rTMS (LI-rTMS), administered as an intermittent theta burst stimulation, but not as a continuous theta burst or 10 Hz stimulation, increased the number of newborn oligodendrocytes in the adult mouse cortex. LI-rTMS did not alter oligodendrogenesis per se, but instead increased cell survival and enhanced myelination. These data suggest that LI-rTMS can be used to noninvasively promote myelin addition to the brain, which has potential implications for the treatment of demyelinating diseases such as multiple sclerosis.


Assuntos
Encéfalo/fisiologia , Oligodendroglia/fisiologia , Estimulação Magnética Transcraniana , Animais , Encéfalo/citologia , Tamanho Celular , Sobrevivência Celular/fisiologia , Feminino , Masculino , Camundongos Transgênicos , Neurogênese/fisiologia , Oligodendroglia/citologia , Distribuição Aleatória , Estimulação Magnética Transcraniana/métodos
17.
Brain Tumor Pathol ; 36(2): 63-73, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968276

RESUMO

Glioblastoma (GBM) is a major malignant brain tumor developing in adult brain white matter, characterized by rapid growth and invasion. GBM cells spread into the contralateral hemisphere, even during early tumor development. However, after complete resection of tumor mass, GBM commonly recurs around the tumor removal cavity, suggesting that a microenvironment at the tumor border provides chemo-radioresistance to GBM cells. Thus, clarification of the tumor border microenvironment is critical for improving prognosis in GBM patients. MicroRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass was compared, and five miRNAs showing characteristically higher expression in the tumor border were identified, with the top three related to oligodendrocyte differentiation. Pathologically, oligodendrocyte lineage cells increased in the border, but were rare in tumors. Macrophages/microglia also colocalized in the border area. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, suggesting that OPCs and macrophages/microglia constitute a special microenvironment for GBM cells at the tumor border. The supportive function of OPCs for GBM cells has not been discussed previously. OPCs are indispensable for GBM cells to establish special niches for chemo-radioresistance outside the tumor mass.


Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Células Precursoras de Oligodendrócitos/patologia , Neoplasias Encefálicas/patologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Linhagem da Célula , Humanos , Macrófagos/metabolismo , MicroRNAs/metabolismo , Microglia/patologia , Microglia/fisiologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Células Precursoras de Oligodendrócitos/fisiologia , Oligodendroglia/patologia , Oligodendroglia/fisiologia , Microambiente Tumoral/fisiologia
18.
J Phys Chem Lett ; 10(11): 2857-2861, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31025568

RESUMO

Mid-infrared photothermal microscopy has been suggested as an alternative to conventional infrared microscopy because in addition to the inherent chemical contrast available upon vibrational excitation, it can feasibly achieve spatial resolution at the submicrometer level. Furthermore, it has substantial potential for real-time bioimaging for the observation of cellular dynamics without photodamage or photobleaching of fluorescent labels. We performed real-time imaging of oligodendrocytes to investigate cellular dynamics throughout the life cycle of a cell, revealing details of cell division and apoptosis, as well as cellular migration. In the case of live neurons, we observed a photothermal contrast associated with traveling protein complexes on an axon, which correspond to the transport of vesicles from the cell body to the dendritic branches of the neuron through the cytoskeleton. We anticipate that mid-infrared photothermal imaging will be of great use for gaining insights into the field of biophysical science, especially with regard to cellular dynamics and functions.


Assuntos
Neurônios/fisiologia , Oligodendroglia/fisiologia , Animais , Apoptose , Divisão Celular , Movimento Celular , Células Cultivadas , Corantes Fluorescentes/química , Raios Infravermelhos , Cinética , Microscopia de Fluorescência , Imagem Molecular , Neurônios/citologia , Neurônios/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Ratos
19.
Glia ; 67(5): 825-843, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30730593

RESUMO

Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta-analysis of high-throughput datasets to reconstruct a regulatory network underpinning OL differentiation. From this network, we identified families of feedforward loops comprising the transcription factors (TFs) Olig2, Sox10, and Tcf7l2 and their targets. Among the targets, we found eight other TFs related to OL differentiation, suggesting a hierarchical architecture in which some TFs (Olig2, Sox10, and Tcf7l2) regulate via feedforward loops the expression of others (Sox2, Sox6, Sox11, Nkx2-2, Nkx6-2, Hes5, Myt1, and Myrf). Model simulations with a kinetic model reproduced the mechanisms of OL differentiation only when in the model, Sox10-mediated repression of Tcf7l2 by miR-338/miR-155 was introduced, a prediction confirmed in genetic functional experiments. Additional model simulations suggested that OLs from dorsal regions emerge through BMP/Sox9 signaling.


Assuntos
Diferenciação Celular/fisiologia , Redes Reguladoras de Genes , Modelos Biológicos , Dinâmica não Linear , Oligodendroglia/fisiologia , Animais , Simulação por Computador , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo
20.
Glia ; 67(7): 1229-1239, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30734358

RESUMO

Oligodendrocytes differentiate from oligodendrocyte progenitor cells (OPCs) in response to distinct extracellular signals. This process requires changes in gene expression resulting from the interplay between transcription factors and epigenetic modulators. Extracellular signals include chemical and physical stimuli. This review focuses on the signaling mechanisms activated in oligodendrocyte progenitors in response to mechanical forces. Of particular interest is a better understanding on how these forces are transduced into the OPC nuclei and subsequently reshape their epigenetic landscape. Here we will introduce the concept of epigenetic regulation of gene expression, first in general and then focusing on the oligodendrocyte lineage. We will then review the current literature on mechano-transduction in distinct cell types, followed by pathways identified in myelinating oligodendrocytes and their progenitors. Overall, the reader will be provided with a comprehensive review of the signaling pathways which allow oligodendrocyte progenitors to "sense" physical forces and transduce them into patterns of gene expression.


Assuntos
Núcleo Celular/metabolismo , Mecanotransdução Celular/fisiologia , Células Precursoras de Oligodendrócitos/fisiologia , Oligodendroglia/fisiologia , Animais , Fenômenos Biomecânicos/fisiologia , Diferenciação Celular/fisiologia , Núcleo Celular/genética , Epigênese Genética/fisiologia , Expressão Gênica , Humanos
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