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1
Facchinetti, Roberta, Marta Valenza, Chiara Gomiero, Giulia Federica Mancini, Luca Steardo, Patrizia Campolongo et Caterina Scuderi. « Co-Ultramicronized Palmitoylethanolamide/Luteolin Restores Oligodendrocyte Homeostasis via Peroxisome Proliferator-Activated Receptor-α in an In Vitro Model of Alzheimer’s Disease ». Biomedicines 10, no 6 (26 mai 2022) : 1236. http://dx.doi.org/10.3390/biomedicines10061236.
Texte intégralRésumé :
Oligodendrocytes are cells fundamental for brain functions as they form the myelin sheath and feed axons. They perform these critical functions thanks to the cooperation with other glial cells, mainly astrocytes. The astrocyte/oligodendrocyte crosstalk needs numerous mediators and receptors, such as peroxisome proliferator-activated receptors (PPARs). PPAR agonists promote oligodendrocyte precursor cells (OPCs) maturation in myelinating oligodendrocytes. In the Alzheimer’s disease brain, deposition of beta-amyloid (Aβ) has been linked to several alterations, including astrogliosis and changes in OPCs maturation. However, very little is known about the molecular mechanisms. Here, we investigated for the first time the maturation of OPCs co-cultured with astrocytes in an in vitro model of Aβ1–42 toxicity. We also tested the potential beneficial effect of the anti-inflammatory and neuroprotective composite palmitoylethanolamide and luteolin (co-ultra PEALut), which is known to engage the isoform alfa of the PPARs. Our results show that Aβ1–42 triggers astrocyte reactivity and inflammation and reduces the levels of growth factors important for OPCs maturation. Oligodendrocytes indeed show low cell surface area and few arborizations. Co-ultra PEALut counteracts the Aβ1–42-induced inflammation and astrocyte reactivity preserving the morphology of co-cultured oligodendrocytes through a mechanism that in some cases involves PPAR-α. This is the first evidence of the negative effects exerted by Aβ1–42 on astrocyte/oligodendrocyte crosstalk and discloses a never-explored co-ultra PEALut ability in restoring oligodendrocyte homeostasis.
2
Seil, Fredrick J. « Tissue Culture Models of Myelination After Oligodendrocyte Transplantation ». Journal of Neural Transplantation 1, no 2 (1989) : 49–55. http://dx.doi.org/10.1155/np.1989.49.
Texte intégralRésumé :
Studies of myelination after transplantation of mature oligodendrocytes to cerebellar cultures in which oligodendrocyte maturation and myelination had been irreversibly inhibited by exposure to cytosine arabinoside were reviewed. Transplanted oligodendrocytes were derived from three sources, including cerebellar explants treated with kainic acid, dissociated oligodendrocyte cultures, and optic nerve fragments. Oligodendrocytes from all sources migrated into the host explants and myelinated appropriate axons. The time of appearance of myelin and the percentage of host cultures myelinated differed for the three sources of oligodendrocytes, however. Myelin was visible earliest and in the highest percentage of host explants transplanted with cultured dissociated oligodendrocytes, which were presumably the most free to migrate into the host tissue, and latest and in the lowest percentage of host cultures transplanted with optic nerve, from which oligodendrocytes were presumably least free to migrate. Some myelin-like membranes unassociated with axons appeared in cerebellar cultures transplanted with cultured dissociated oligodendrocytes, and not in cerebellar explants transplanted with oligodendrocytes from other sources. The formation of such myelin-like membranes was interpreted as a manifestation of oligodendrocyte hyperreactivity induced by culture in isolation.
3
Nadon, N. L., I. D. Duncan et L. D. Hudson. « A point mutation in the proteolipid protein gene of the ‘shaking pup’ interrupts oligodendrocyte development ». Development 110, no 2 (1 octobre 1990) : 529–37. http://dx.doi.org/10.1242/dev.110.2.529.
Texte intégralRésumé :
The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.
4
Louis, JC, E. Magal, S. Takayama et S. Varon. « CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death ». Science 259, no 5095 (29 janvier 1993) : 689–92. http://dx.doi.org/10.1126/science.8430320.
Texte intégralRésumé :
A proportion of developing oligodendrocytes undergo natural cell death by apoptosis, and mature oligodendrocytes die, either by apoptosis or necrosis, in response to injurious signals such as cytotoxic cytokines and complement. Ciliary neurotrophic factor (CNTF), a trophic factor found in astrocytes in the central nervous system (CNS), promoted the survival and maturation of cultured oligodendrocytes. This trophic factor also protected oligodendrocytes from death induced by tumor necrosis factors (apoptosis) but not against complement (necrosis). These results suggest that CNTF functions in the survival of oligodendrocytes during development and may lead to therapeutic approaches for degenerative diseases of the CNS that involve oligodendrocyte destruction.
5
Ono, K., R. Bansal, J. Payne, U. Rutishauser et R. H. Miller. « Early development and dispersal of oligodendrocyte precursors in the embryonic chick spinal cord ». Development 121, no 6 (1 juin 1995) : 1743–54. http://dx.doi.org/10.1242/dev.121.6.1743.
Texte intégralRésumé :
Oligodendrocytes, the myelinating cells of the vertebrate CNS, originally develop from cells of the neuroepithelium. Recent studies suggest that spinal cord oligodendrocyte precursors are initially localized in the region of the ventral ventricular zone and subsequently disperse throughout the spinal cord. The characteristics of these early oligodendrocyte precursors and their subsequent migration has been difficult to assay directly in the rodent spinal cord due to a lack of appropriate reagents. In the developing chick spinal cord, we show that oligodendrocyte precursors can be specifically identified by labeling with O4 monoclonal antibody. In contrast to rodent oligodendrocyte precursors, which express O4 immunoreactivity only during the later stages of maturation, in the chick O4 immunoreactivity appears very early and its expression is retained through cellular maturation. In embryos older than stage 35, O4+ cells represent the most immature, self-renewing, cells of the chick spinal cord oligodendrocyte lineage. In the intact chick spinal cord, the earliest O4+ cells are located at the ventral ventricular zone where they actually contribute to the ventricular lining of the central canal. The subsequent migration of O4+ cells into the dorsal region of the spinal cord temporally correlates with the capacity of isolated dorsal spinal cord to generate oligodendrocytes in vitro. Biochemical analysis suggests O4 labels a POA-like antigen on the surface of chick spinal cord oligodendrocyte precursors. These studies provide direct evidence for the ventral ventricular origin of spinal cord oligodendrocytes, and suggest that this focal source of oligodendrocytes is a general characteristic of vertebrate development.
6
Mariyath, Mubeena P. M., Mehdi H. Shahi, Shirin Farheen, Mohd Tayyab, Nabeela Khanam et Asif Ali. « Novel Homeodomain Transcription Factor Nkx2.2 in the Brain Tumor Development ». Current Cancer Drug Targets 20, no 5 (5 juin 2020) : 335–40. http://dx.doi.org/10.2174/1568009618666180102111539.
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Background: Complex central nervous system (CNS) is made up of neuronal cells and glial cells. Cells of central nervous system are able to regenerate after injury and during repairing. Sonic hedgehog pathway initiated by Shh-N a glycoprotein plays vital role in CNS patterning growth, development and now tumorigenesis. Nkx2.2 homeodomain transcription factor is an effecter molecule, which is positively regulated by Shh during normal growth. Nkx2.2 is essential for V3 domain specification during neural tube patterning at embryonic stage. MBP + oligodendrocytes are differentiated from progenitor cells which express Olig2. Nx2.2 is co-expressed with Olig2 in oligodendrocytes and is essential for later stage of oligodendrocyte maturation. Objective: This review paper explores the potential role of Nkx2.2 transcription factor in glioblastoma development. Conclusion: Shh pathway plays a vital role in oligodendrocytes differentiation and Nkx2.2 transcription factor is essential for oligodendrocytes differentiation and maturation. Intriguingly, down regulation of Nkx2.2 transcription factor with aberrant Shh signaling pathway is reported in glioma samples. So here it is suggested that Nkx2.2 expression pattern could be used as a potential biomarker for the early diagnosis of glioma.
7
Vostrikov, Victor, et Natalya Uranova. « Age-Related Increase in the Number of Oligodendrocytes Is Dysregulated in Schizophrenia and Mood Disorders ». Schizophrenia Research and Treatment 2011 (2011) : 1–10. http://dx.doi.org/10.1155/2011/174689.
Texte intégralRésumé :
The postnatal maturation of the human prefrontal cortex is associated with substantial increase of number of oligodendrocytes. Previously, we reported decreased numerical density of oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. To gain further understanding of the role oligodendrocytes in pathogenesis of schizophrenia and mood disorders, we examined the effect of the age on the number of oligodendrocytes in the prefrontal cortex in schizophrenia, bipolar disorder, and major depressive disorder. We revealed the age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA10 and BA 9 in normal controls but not in schizophrenia, bipolar disorder, and major depressive disorder. The absence of normal increase in the number of oligodendrocytes in gray and white matter with age in schizophrenia and mood disorders suggests that age-related process of oligodendrocyte increase is dysregulated in schizophrenia and mood disorders.
8
Aberle, Tim, Sandra Piefke, Simone Hillgärtner, Ernst R. Tamm, Michael Wegner et Melanie Küspert. « Transcription factor Zfp276 drives oligodendroglial differentiation and myelination by switching off the progenitor cell program ». Nucleic Acids Research 50, no 4 (7 février 2022) : 1951–68. http://dx.doi.org/10.1093/nar/gkac042.
Texte intégralRésumé :
Abstract In oligodendrocytes of the vertebrate central nervous system a complex network of transcriptional regulators is required to ensure correct and timely myelination of neuronal axons. Here we identify Zfp276, the only mammalian ZAD-domain containing zinc finger protein, as a transcriptional regulator of oligodendrocyte differentiation and central myelination downstream of Sox10. In the central nervous system, Zfp276 is exclusively expressed in mature oligodendrocytes. Oligodendroglial deletion of Zfp276 led to strongly reduced expression of myelin genes in the early postnatal mouse spinal cord. Retroviral overexpression of Zfp276 in cultured oligodendrocyte precursor cells induced precocious expression of maturation markers and myelin genes, further supporting its role in oligodendroglial differentiation. On the molecular level, Zfp276 directly binds to and represses Sox10-dependent gene regulatory regions of immaturity factors and functionally interacts with the transcriptional repressor Zeb2 to enable fast transition of oligodendrocytes to the myelinating stage.
9
Rosko, Lauren, Victoria N. Smith, Reiji Yamazaki et Jeffrey K. Huang. « Oligodendrocyte Bioenergetics in Health and Disease ». Neuroscientist 25, no 4 (20 août 2018) : 334–43. http://dx.doi.org/10.1177/1073858418793077.
Texte intégralRésumé :
The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person’s total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.
10
Ferraresi, S., I. Lorenzetti, R. Nemni, J. Kamholz, ML Feltri et L. Wrabetz. « Toward a transgenic mouse model of remyelination ». Multiple Sclerosis Journal 3, no 2 (avril 1997) : 80–83. http://dx.doi.org/10.1177/135245859700300204.
Texte intégralRésumé :
The molecular mechanisms necessary for remyelination by oligodendrocytes remain unexplored. We previously characterized a myelin basic protein promoter-lacZ (MBP-lacZ) transgene whose expression is regulated uniquely during development, and also in pathological situations, suggesting that it may be a useful reporter of molecular mechanisms during remyelination. As a first step toward creating a transgenic mouse model of remyelination, we cultured oligodendrocytes from these transgenic mice and showed that expression of MBP-lacZ appeared in parallel with a marker of oligodendrocyte maturation, galactocerebroside (GC). In addition, basic fibroblast growth factor blocked the expression of both MBP-lacZ and GC in these cells. Therefore, expression of MBP-lacZ reflects not only the developmental stage of oligodendrocytes, but also extrinsic influences on oligodendrocytes. These data suggest that MBP-lacZ may be a useful marker in transgenic mouse models of remyelination.
11
Kawamura, Atsuki, Yuta Katayama, Masaaki Nishiyama, Hirotaka Shoji, Kota Tokuoka, Yoshifumi Ueta, Mariko Miyata et al. « Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice ». Human Molecular Genetics 29, no 8 (6 mars 2020) : 1274–91. http://dx.doi.org/10.1093/hmg/ddaa036.
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Abstract Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.
12
Russell, Lauren N., et Kyle J. Lampe. « Engineering Biomaterials to Influence Oligodendroglial Growth, Maturation, and Myelin Production ». Cells Tissues Organs 202, no 1-2 (2016) : 85–101. http://dx.doi.org/10.1159/000446645.
Texte intégralRésumé :
Millions of people suffer from damage or disease to the nervous system that results in a loss of myelin, such as through a spinal cord injury or multiple sclerosis. Diminished myelin levels lead to further cell death in which unmyelinated neurons die. In the central nervous system, a loss of myelin is especially detrimental because of its poor ability to regenerate. Cell therapies such as stem or precursor cell injection have been investigated as stem cells are able to grow and differentiate into the damaged cells; however, stem cell injection alone has been unsuccessful in many areas of neural regeneration. Therefore, researchers have begun exploring combined therapies with biomaterials that promote cell growth and differentiation while localizing cells in the injured area. The regrowth of myelinating oligodendrocytes from neural stem cells through a biomaterials approach may prove to be a beneficial strategy following the onset of demyelination. This article reviews recent advancements in biomaterial strategies for the differentiation of neural stem cells into oligodendrocytes, and presents new data indicating appropriate properties for oligodendrocyte precursor cell growth. In some cases, an increase in oligodendrocyte differentiation alongside neurons is further highlighted for functional improvements where the biomaterial was then tested for increased myelination both in vitro and in vivo.
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Lewkowicz, Natalia, Paweł Piątek, Magdalena Namiecińska, Małgorzata Domowicz, Radosław Bonikowski, Janusz Szemraj, Patrycja Przygodzka, Mariusz Stasiołek et Przemysław Lewkowicz. « Naturally Occurring Nervonic Acid Ester Improves Myelin Synthesis by Human Oligodendrocytes ». Cells 8, no 8 (29 juillet 2019) : 786. http://dx.doi.org/10.3390/cells8080786.
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The dysfunction of oligodendrocytes (OLs) is regarded as one of the major causes of inefficient remyelination in multiple sclerosis, resulting gradually in disease progression. Oligodendrocytes are derived from oligodendrocyte progenitor cells (OPCs), which populate the adult central nervous system, but their physiological capability to myelin synthesis is limited. The low intake of essential lipids for sphingomyelin synthesis in the human diet may account for increased demyelination and the reduced efficiency of the remyelination process. In our study on lipid profiling in an experimental autoimmune encephalomyelitis brain, we revealed that during acute inflammation, nervonic acid synthesis is silenced, which is the effect of shifting the lipid metabolism pathway of common substrates into proinflammatory arachidonic acid production. In the experiments on the human model of maturating oligodendrocyte precursor cells (hOPCs) in vitro, we demonstrated that fish oil mixture (FOM) affected the function of hOPCs, resulting in the improved synthesis of myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein, as well as sphingomyelin. Additionally, FOM reduces proinflammatory cytokines and chemokines, and enhances fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) synthesis by hOPCs was also demonstrated. Based on these observations, we propose that the intake of FOM rich in the nervonic acid ester may improve OL function, affecting OPC maturation and limiting inflammation.
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Velasco-Estevez, Maria, Nina Koch, Ilona Klejbor, Stephane Laurent, Kumlesh K. Dev, Andrzej Szutowicz, Andreas W. Sailer et Aleksandra Rutkowska. « EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model ». International Journal of Molecular Sciences 22, no 9 (21 avril 2021) : 4342. http://dx.doi.org/10.3390/ijms22094342.
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The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.
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Maiuolo, Jessica, Micaela Gliozzi, Vincenzo Musolino, Cristina Carresi, Saverio Nucera, Miriam Scicchitano, Federica Scarano et al. « Environmental and Nutritional “Stressors” and Oligodendrocyte Dysfunction : Role of Mitochondrial and Endoplasmatic Reticulum Impairment ». Biomedicines 8, no 12 (30 novembre 2020) : 553. http://dx.doi.org/10.3390/biomedicines8120553.
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Oligodendrocytes are myelinating cells of the central nervous system which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, insulating them and facilitating nerve conduction through saltatory propagation. The myelination process requires the consumption a large amount of energy and a high metabolic turnover. Mitochondria are essential organelles which regulate many cellular functions, including energy production through oxidative phosphorylation. Any mitochondrial dysfunction impacts cellular metabolism and negatively affects the health of the organism. If the functioning of the mitochondria is unbalanced, the myelination process is impaired. When myelination has finished, oligodendrocyte will have synthesized about 40% of the total lipids present in the brain. Since lipid synthesis occurs in the cellular endoplasmic reticulum, the dysfunction of this organelle can lead to partial or deficient myelination, triggering numerous neurodegenerative diseases. In this review, the induced malfunction of oligodendrocytes by harmful exogenous stimuli has been outlined. In particular, the effects of alcohol consumption and heavy metal intake are discussed. Furthermore, the response of the oligodendrocyte to excessive mitochondrial oxidative stress and to the altered regulation of the functioning of the endoplasmic reticulum will be explored.
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Soomro, Shahid Hussain, Jifu Jie et Hui Fu. « Oligodendrocytes Development and Wnt Signaling Pathway ». International Journal of Human Anatomy 1, no 3 (29 octobre 2018) : 17–35. http://dx.doi.org/10.14302/issn.2577-2279.ijha-18-2407.
Texte intégralRésumé :
Oligodendrocytes are specialized glial cell in central nervous system (CNS) responsible for the formation of myelin sheath around the axon. Oligodendrocyte proliferation and differentiation is regulated by Wnt signaling pathway, at various stages. However, different study groups have described controversial conclusions about the effect of Wnt on oligodendrocytes precursor cells (OPCs) development. Initially it has been proposed that Wnt pathway negatively regulates the OPCs proliferation and differentiation but recently some studies have described that Wnt promotes the differentiation of OPCs. After carefully reviewing the literature, we believe that Wnt play multiple roles in OPCs differentiation and its function is time (stage) and dose sensitive. Low to moderate activation of Wnt promotes OPC development, while too much or too low is inhibitory. Current evidences also suggested that in early developmental stages, Wnt inhibits the OPCs formation from neural progenitors and differentiation into immature oligodendrocytes. But in late stages Wnt plays promoting role in differentiation and maturation of oligodendrocytes. This review summarized the updated information regarding the critical role of Wnt signaling cascade in proliferation and differentiation of OPCs.
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Trajkovic, Katarina, Ajit Singh Dhaunchak, José T. Goncalves, Dirk Wenzel, Anja Schneider, Gertrude Bunt, Klaus-Armin Nave et Mikael Simons. « Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites ». Journal of Cell Biology 172, no 6 (6 mars 2006) : 937–48. http://dx.doi.org/10.1083/jcb.200509022.
Texte intégralRésumé :
During vertebrate brain development, axons are enwrapped by myelin, an insulating membrane produced by oligodendrocytes. Neuron-derived signaling molecules are temporally and spatially required to coordinate oligodendrocyte differentiation. In this study, we show that neurons regulate myelin membrane trafficking in oligodendrocytes. In the absence of neurons, the major myelin membrane protein, the proteolipid protein (PLP), is internalized and stored in late endosomes/lysosomes (LEs/Ls) by a cholesterol-dependent and clathrin-independent endocytosis pathway that requires actin and the RhoA guanosine triphosphatase. Upon maturation, the rate of endocytosis is reduced, and a cAMP-dependent neuronal signal triggers the transport of PLP from LEs/Ls to the plasma membrane. These findings reveal a fundamental and novel role of LEs/Ls in oligodendrocytes: to store and release PLP in a regulated fashion. The release of myelin membrane from LEs/Ls by neuronal signals may represent a mechanism to control myelin membrane growth.
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O'Meara, Ryan W., John-Paul Michalski et Rashmi Kothary. « Integrin Signaling in Oligodendrocytes and Its Importance in CNS Myelination ». Journal of Signal Transduction 2011 (20 décembre 2011) : 1–11. http://dx.doi.org/10.1155/2011/354091.
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Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.
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Schmitt, Andrea, Laura Tatsch, Alisa Vollhardt, Thomas Schneider-Axmann, Florian J. Raabe, Lukas Roell, Helmut Heinsen, Patrick R. Hof, Peter Falkai et Christoph Schmitz. « Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia : A Replication Study ». Cells 11, no 20 (15 octobre 2022) : 3242. http://dx.doi.org/10.3390/cells11203242.
Texte intégralRésumé :
Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.
20
Qi, Yingchuan, Jun Cai, Yuanyuan Wu, Rui Wu, Jeffrey Lee, Hui Fu, Mahendra Rao, Lori Sussel, John Rubenstein et Mengsheng Qiu. « Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor ». Development 128, no 14 (15 juillet 2001) : 2723–33. http://dx.doi.org/10.1242/dev.128.14.2723.
Texte intégralRésumé :
Oligodendrocytes are derived from glial precursors that arise from the ventral neural tube early in development. In the developing chicken CNS, oligodendrocyte progenitors selectively express Nkx2.2 homeodomain transcription factor, raising the possibility that Nkx2.2 may directly regulate oligogliogenesis. In this study, we have examined Nkx2.2 expression in rodent glial precursors and studied the effect of a loss of Nkx2.2 on oligodendrocyte and astrocyte differentiation. We show that Nkx2.2 is also expressed in mammalian oligodendrocyte progenitors and that the differentiation of MBP-positive and PLP-DM20-positive oligodendrocytes is dramatically retarded in Nkx2.2-null mutants along the entire rostrocaudal axis. In contrast, no effect is seen on astrocytic differentiation. Interestingly, absence of Nkx2.2 expression leads to a ventral expansion of the Olig1/Olig2 expression in neuroepithelial cells into the Nkx2.2 domain and a consequent increase in the production of Olig1/Olig2-positive and platelet-derived growth factor receptor α-positive oligodendrocyte progenitors. These results strongly suggest that Nkx2.2 regulates the differentiation and/or maturation, but not the initial specification, of oligodendrocyte progenitors. Consistent with this suggestion, overproduction of Nkx2.2 protein in fibroblast cells can induce gene expression from the proteolipid protein promoter.
21
Tiane, Assia, Melissa Schepers, Ben Rombaut, Raymond Hupperts, Jos Prickaerts, Niels Hellings, Daniel van den Hove et Tim Vanmierlo. « From OPC to Oligodendrocyte : An Epigenetic Journey ». Cells 8, no 10 (11 octobre 2019) : 1236. http://dx.doi.org/10.3390/cells8101236.
Texte intégralRésumé :
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.
22
Richter-Landsberg, Christiane. « Protein aggregate formation in oligodendrocytes : tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration ». Biological Chemistry 397, no 3 (1 mars 2016) : 185–94. http://dx.doi.org/10.1515/hsz-2015-0157.
Texte intégralRésumé :
Abstract Oligodendrocytes are dependent on an intact, dynamic microtubule (MT) network, which participates in the elaboration and stabilization of myelin forming extensions, and is essential for cellular sorting processes. The microtubule-associated protein tau is constituent of oligodendrocytes. During culture maturation it is developmentally regulated and important for MT stability, MT formation and intracellular trafficking. Downregulation of tau impairs process outgrowth and the transport of myelin basic protein (MBP) mRNA to the cell periphery. Cells fail to differentiate into MBP-expressing, sheet-forming oligodendrocytes. Tau-positive inclusions originating in oligodendrocytes and white matter pathology are prominent in frontotemporal dementias, such as Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6. In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.
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Ercan, Ebru, Juliette M. Han, Alessia Di Nardo, Kellen Winden, Min-Joon Han, Leonie Hoyo, Afshin Saffari, Andrew Leask, Daniel H. Geschwind et Mustafa Sahin. « Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex ». Journal of Experimental Medicine 214, no 3 (9 février 2017) : 681–97. http://dx.doi.org/10.1084/jem.20160446.
Texte intégralRésumé :
Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non–cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.
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Kim, Min Joung, et Steven Petratos. « Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions ». Stem Cells International 2019 (30 avril 2019) : 1–13. http://dx.doi.org/10.1155/2019/5496891.
Texte intégralRésumé :
Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T3 availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions.
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Damiano, Simona, Giuliana La Rosa, Concetta Sozio, Gina Cavaliere, Giovanna Trinchese, Maddalena Raia, Roberto Paternò, Maria Pina Mollica, Vittorio Enrico Avvedimento et Mariarosaria Santillo. « 5-Hydroxytryptamine Modulates Maturation and Mitochondria Function of Human Oligodendrocyte Progenitor M03-13 Cells ». International Journal of Molecular Sciences 22, no 5 (5 mars 2021) : 2621. http://dx.doi.org/10.3390/ijms22052621.
Texte intégralRésumé :
Inside the adult CNS, oligodendrocyte progenitor cells (OPCS) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to the lesion areas where they undergo differentiation and myelin synthesis. Serotonin (5-hydroxytryptamine, 5-HT) is involved in OLs’ development and myelination, but so far the molecular mechanisms involved or the effects of 5-HT on mitochondria function have not yet been well documented. Our data show that 5-HT inhibits migration and proliferation committing cells toward differentiation in an immortalized human oligodendrocyte precursor cell line, M03-13. Migration blockage is mediated by reactive oxygen species (ROS) generation since antioxidants, such as Vit C and Cu-Zn superoxide dismutase, prevent the inhibitory effects of 5-HT on cell migration. 5-HT inhibits OPC migration and proliferation and increases OL phenotypic markers myelin basic protein (MBP) and Olig-2 via protein kinase C (PKC) activation since the inhibitor of PKC, bis-indolyl-maleimide (BIM), counteracts 5-HT effects. NOX inhibitors as well, reverse the effects of 5-HT, indicating that 5-HT influences the maturation process of OPCs by NOX-dependent ROS production. Finally, 5-HT increases mitochondria function and antioxidant activity. The identification of the molecular mechanisms underlying the effects of 5-HT on maturation and energy metabolism of OPCs could pave the way for the development of new treatments for autoimmune demyelinating diseases such as Multiple Sclerosis where oligodendrocytes are the primary target of immune attack.
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Schuster, Kristen H., Alexandra F. Putka et Hayley S. McLoughlin. « Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture ». Cells 11, no 16 (22 août 2022) : 2615. http://dx.doi.org/10.3390/cells11162615.
Texte intégralRésumé :
Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis.
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Dollé, Jean-Pierre, Rene S. Schloss et Martin L. Yarmush. « PPAR Agonists and 3D Alginate Encapsulation Accelerate Oligodendrocyte Differentiation of Mouse Embryonic Stem Cells ». Nano LIFE 06, no 01 (mars 2016) : 1650003. http://dx.doi.org/10.1142/s1793984416500033.
Texte intégralRésumé :
Cellular replacement therapies for myelin disorders require large numbers of cells and relatively mature oligodendrocytes. Oligodendrocyte differentiation from a pluripotent state often involves long protracted protocols. In this study, we investigated the effect that activation of peroxisome proliferator activator receptors (PPAR) alpha, delta and gamma would have on oligodendrocyte differentiation of mouse embryonic stem (mES) cells. Using a two-dimensional (2D) differentiation platform, oligodendrocyte differentiation stalled at the immature oligodendrocyte stage, i.e., CNPase positive cells. When PPAR agonists for alpha, delta and gamma were added, oligodendrocyte differentiation was accelerated with higher numbers of O1 and CNPase positive cells being detected. PPAR agonist addition also resulted in phenotypic changes with alpha agonist addition resulting in an increase in process length compared to control with some increased secondary branching, delta agonist addition resulted in longer primary process length, and gamma agonist addition resulted in a larger cell soma and more tertiary branching patterns. Placing mES cells into a three-dimensional (3D) alginate nanoporous microcapsule environment, we were able to further mature cells to a myelin basic protein (MBP) expressing stage. The exposure of cells to PPAR agonists within the alginate microcapsules resulted in accelerated maturation with PPAR delta in particular showing a sustained high expression of MBP. The combined effect of PPAR activation in a 3D environment demonstrates a relatively simple and efficient method to differentiate mES cells into mature oligodendrocytes.
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Noll, E., et R. H. Miller. « Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline region in the embryonic rat spinal cord ». Development 118, no 2 (1 juin 1993) : 563–73. http://dx.doi.org/10.1242/dev.118.2.563.
Texte intégralRésumé :
The precursors for oligodendrocytes, the myelinating cells of the vertebrate CNS, appear to be initially restricted to ventral regions of the embryonic rat spinal cord. These cells subsequently populate dorsal spinal cord regions where they acquire the mature characteristics of oligodendrocytes. To determine the location and timing of proliferation of oligodendrocyte precursors in the ventral spinal cord, and to map their pathways of migration in vivo, an assay that identifies mitotic cells was used in conjunction with antibodies that distinguish astrocytes, oligodendrocytes and their precursors. Between E16.5 and E18.5, two hours after a maternal injection of BrdU, the majority of proliferating cells were located in a discrete cluster at the ventral ventricular zone dorsal to the ventral midline region of the developing spinal cord. By contrast, 12–24 hours following a BrdU injection at E16.5, increasing numbers of labeled cells were seen in the dorsal and more lateral locations of the spinal cord. These observations suggest that BrdU-labeled ventral ventricular cells, or their progeny migrate dorsally and laterally during subsequent spinal cord development. To determine the nature of these proliferating cells, cultures of dorsal and ventral spinal cord from BrdU-labeled animals were double-labeled with antibodies that identify oligodendrocytes or astrocytes and anti-BrdU. In dorsal spinal cord cultures derived from animals that had received a single injection of BrdU at E16.5, the majority of proliferating cells differentiated into astrocytes while, in ventrally derived cultures from the same animals, the majority of proliferating cells differentiated into oligodendrocytes. In dorsal cultures prepared from animals that received multiple injections of BrdU between E16.5 and E18.5, many more cells were labeled with BrdU and approximately half of these differentiated into oligodendrocytes. These observations suggest that during embryonic development proliferating oligodendrocyte precursors are initially located at the ventral ventricular zone dorsal to the ventral midline region of the spinal cord and during subsequent maturation these cells or their progeny migrated dorsally in the ventricular region of the spinal cord, and laterally to reside in the developing white matter.
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Suzumura, Akio, et Donald H. Silberberg. « Lymphokines facilitate maturation of oligodendrocytes in vitro ». Brain Research 480, no 1-2 (février 1989) : 51–57. http://dx.doi.org/10.1016/0006-8993(89)91565-5.
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Iacobas, Sanda, et Dumitru A. Iacobas. « Astrocyte proximity modulates the myelination gene fabric of oligodendrocytes ». Neuron Glia Biology 6, no 3 (août 2010) : 157–69. http://dx.doi.org/10.1017/s1740925x10000220.
Texte intégralRésumé :
Extensive literature documented that astrocytes release neurotransmitters, cytokines and other signaling molecules to modulate migration, maturation and myelin synthesis of oligodendrocytes through mechanisms primarily converging on cytosolic [Ca2+] transients. Considering the long-term effects, it is expected that astrocyte-conditioned medium is a major regulator of gene expression in oligodendrocytes even in the absence of cytosol-to-cytosol communication via astrocyte–oligodendrocyte gap junction channels. Indeed, by comparing the transcriptomes of immortalized precursor oligodendrocyte (Oli-neu) cells when cultured alone and co-cultured with non-touching astrocytes we found profound changes in the gene expression level, control and networking. Remarkably, the astrocyte proximity was more effective in remodeling the myelination (MYE) gene fabric and its control by cytokine receptor (CYR)-modulated intercellular Ca2+-signaling (ICS) transcriptomic network than the dibutyryl-cAMP (db-cAMP) treatment-induced transformation into myelin-associated glycoprotein-positive oligodendrocyte-like cells. Moreover, astrocyte proximity up-regulated 37 MYE genes and switched on another 14 MYE, 23 ICS and 4 CYR genes, enhancing the roles of the leukemia inhibitory factor receptor and connexins Cx29 and Cx47. The novel prominent gene analysis identified the enhancer of zeste homolog 2 as the most relevant MYE gene in the astrocyte proximity, notch gene homolog 1 in control and B-cell leukemia/lymphoma 2 in differentiated Oli-neu cells.
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Li, T., Y. Xie et W. Ji. « 199 DIFFERENTIATION OF HIGHLY ENRICHED OLIGODENDROCYTE PRECURSORS AND MATURE OLIGODENDROCYTES FROM RHESUS MONKEY EMBRYONIC STEM CELLS ». Reproduction, Fertility and Development 18, no 2 (2006) : 207. http://dx.doi.org/10.1071/rdv18n2ab199.
Texte intégralRésumé :
Generating homologous oligodendrocytes are required for studying the molecular mechanisms of oligodendrogliogenesis and for providing donor cells for transplantation therapies. Previous studies have shown that embryonic stem (ES) cells can be induced to generate neural stem cells with many kinds of culture systems; however, few or no oligodendrocytes were obtained from these culture systems. Here we present a simple method containing five steps for obtaining highly enriched oligodendrocyte precursors (75 � 6.8%) and mature oligodendrocytes (81 � 8.6%) from rhesus monkey embryonic stem (rES) cells. We expanded rES cells on a feeder layer of irradiated MESF (ear skin fibroblasts from a one-week-old rhesus monkey), formed embryoid bodies (EBs), promoted Day 9 (3 days in hanging drop and 6 days in suspension) differentiation into highly enriched (90.2 � 6.1%) neural progenitors (NPs) with hepatocyte growth factor (HGF) and G5 supplement [containing 5 ng/mL (bFGF) and 10 ng/mL epidermal growth factor (EGF)], purified NPs with 0.0625% trypsin in 0.04% EDTA (98% of cells were nestin-positive), amplified those progenitors in HGF and G5 media for two months, and then induced oligodendrocyte precursors differentiation in the absence of G5, but in the presence of 20 ng/mL HGF for 2 days. To obtain terminal oligodendrocytes, neurospheres cultured for 2 months were plated on laminin-coated plates for 3 weeks in the presence of HGF. The results showed that differentiated cells expressed myelin basic protein (MBP) and had typical mature oligodendrocyte morphology. Our studies also revealed that HGF significantly increased the NP proliferation speed (P < 0.05) by both decreasing cell apoptosis rate (P < 0.05) and shortening cell cycle time (P < 0.05) in the presence of G5. Additionally, HGF promoted oligodendrocyte maturation by increasing the length and number of branches and the expression of MBP. To test whether the original HGF had similar functions for oligodendrocyte specification, a series of experiments were evaluated by adding HGF or G5 to differentiation or expansion media at different differentiation stages. The results demonstrated that the ability of HGF responsiveness to initiate oligodendrocyte differentiation was regulated by G5 and by HGF alone without G5-induced rES cell differentiation into neurons. Further studies showed that the crucial time point of G5 action was from EBs to NPs; the early addition of HGF to EBs in the presence of G5 increased oligodendrocyte differentiation rate, but was not necessary, and the treatment during the first 2 days was enough to produce a similar effect; and HGF was required for terminal oligodendrocyte differentiation from NPs. Taken together, these results showed that HGF and G5 cooperatively promote rES cell differentiation into highly enriched oligodendrocyte precursors and mature oligodendrocytes.These observations set the method for obtaining highly enriched oligodendrocytes from ES cells in the nonhuman primate for clinical application and provide a platform to probe the molecular mechanisms that control oligodendrocyte differentiation.
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Mayer, M., K. Bhakoo et M. Noble. « Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro ». Development 120, no 1 (1 janvier 1994) : 143–53. http://dx.doi.org/10.1242/dev.120.1.143.
Texte intégralRésumé :
We have found that CNTF and LIF are pleiotropic modulators of development in the O-2A lineage. Both molecules enhanced the generation of oligodendrocytes in cultures of dividing O-2A progenitors. CNTF and LIF also promoted oligodendrocyte maturation, as determined by expression of myelin basic protein, and could promote oligodendrocyte survival to an extent comparable with insulin-like growth factor-1 or insulin. In addition, LIF and CNTF both promoted the differentiation of O-2A progenitors into type-2 astrocytes but only when applied in the presence of extracellular matrix (EnMx) derived from cultures of endothelial cells. The ability of CNTF and LIF to enhance differentiation of O-2A progenitors along either of the alternative pathways of oligodendrocyte and astrocyte differentiation suggests that these proteins are able to enhance the process of differentiation per se, while the actual path of differentiation promoted is determined by the presence or absence of additional molecules in the extracellular environment.
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Bauch, Juliane, et Andreas Faissner. « The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model ». Cells 11, no 11 (28 mai 2022) : 1773. http://dx.doi.org/10.3390/cells11111773.
Texte intégralRésumé :
Oligodendrocytes are the myelinating cells of the central nervous system. The physiological importance of oligodendrocytes is highlighted by diseases such as multiple sclerosis, in which the myelin sheaths are degraded and the axonal signal transmission is compromised. In a healthy brain, spontaneous remyelination is rare, and newly formed myelin sheaths are thinner and shorter than the former ones. The myelination process requires the migration, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) and is influenced by proteins of the extracellular matrix (ECM), which consists of a network of glycoproteins and proteoglycans. In particular, the glycoprotein tenascin-C (Tnc) has an inhibitory effect on the differentiation of OPCs and the remyelination efficiency of oligodendrocytes. The structurally similar tenascin-R (Tnr) exerts an inhibitory influence on the formation of myelin membranes in vitro. When Tnc knockout oligodendrocytes were applied to an in vitro myelination assay using artificial fibers, a higher number of sheaths per single cell were obtained compared to the wild-type control. This effect was enhanced by adding brain-derived neurotrophic factor (BDNF) to the culture system. Tnr−/− oligodendrocytes behaved differently in that the number of formed sheaths per single cell was decreased, indicating that Tnr supports the differentiation of OPCs. In order to study the functions of tenascin proteins in vivo Tnc−/− and Tnr−/− mice were exposed to Cuprizone-induced demyelination for a period of 10 weeks. Both Tnc−/− and Tnr−/− mouse knockout lines displayed a significant increase in the regenerating myelin sheath thickness after Cuprizone treatment. Furthermore, in the absence of either tenascin, the number of OPCs was increased. These results suggest that the fine-tuning of myelin regeneration is regulated by the major tenascin proteins of the CNS.
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Allinquant, B., S. M. Staugaitis, D. D'Urso et D. R. Colman. « The ectopic expression of myelin basic protein isoforms in Shiverer oligodendrocytes : implications for myelinogenesis. » Journal of Cell Biology 113, no 2 (15 avril 1991) : 393–403. http://dx.doi.org/10.1083/jcb.113.2.393.
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The myelin basic proteins (MBPs) are a set of peripheral membrane polypeptides that are required for the compaction of the major dense line of central nervous system myelin. We have used primary cultures of oligodendrocytes from MBP-deficient shiverer mice as host cells for the expression by cDNA transfection of each of the four major MBP isoforms. The distributions of the encoded polypeptides were studied by immunofluorescence and confocal microscopy and compared with patterns of MBP expression in normal mouse oligodendrocytes in situ and in culture. The exon II-containing 21.5- or 17-kD MBPs were distributed diffusely in the cytoplasm and in the nucleus of the transfectants, closely resembling the patterns obtained in myelinating oligodendrocytes in 9-d-old normal mouse brains. By contrast, the distribution of the 14- and 18.5-kD MBPs in the transfectants was confined to the plasma membrane and mimicked the distribution of MBP in cultures of normal adult oligodendrocytes. Our results strongly suggest that the exon II-containing MBPs are expressed first and exclusively during oligodendrocyte maturation, where they may play a role in the early phase of implementation of the myelination program. In contrast, the 14- and 18.5-kD MBPs that possess strong affinity for the plasma membrane are likely to be the principle inducers of myelin compaction at the major dense line.
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Egawa, Naohiro, Gen Hamanaka, Kelly K. Chung, Hidehiro Ishikawa, Akihiro Shindo, Takakuni Maki, Ryosuke Takahashi, Haruhisa Inoue, Eng H. Lo et Ken Arai. « High Mobility Group A1 Regulates Transcription Levels of Oligodendrocyte Marker Genes in Cultured Oligodendrocyte Precursor Cells ». International Journal of Molecular Sciences 23, no 4 (17 février 2022) : 2236. http://dx.doi.org/10.3390/ijms23042236.
Texte intégralRésumé :
Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Past studies have confirmed the importance of epigenetic system in OPC differentiation to oligodendrocytes. High mobility group A1 (HMGA1) is a small non-histone nuclear protein that binds DNA and modifies the chromatin conformational state. However, it is still completely unknown about the roles of HMGA1 in the process of OPC differentiation. In this study, we prepared primary OPC cultures from the neonatal rat cortex and examined whether the loss- and gain-of-function of HMGA1 would change the mRNA levels of oligodendrocyte markers, such as Cnp, Mbp, Myrf and Plp during the process of OPC differentiation. In our system, the mRNA levels of Cnp, Mbp, Myrf and Plp increased depending on the oligodendrocyte maturation step, but the level of Hmga1 mRNA decreased. When HMGA1 was knocked down by a siRNA approach, the mRNA levels of Cnp, Mbp, Myrf and Plp were smaller in OPCs with Hmga1 siRNA compared to the ones in the control OPCs. On the contrary, when HMGA1 expression was increased by transfection of the Hmga1 plasmid, the mRNA levels of Cnp, Mbp, Myrf and Plp were slightly larger compared to the ones in the control OPCs. These data may suggest that HMGA1 participates in the process of OPC differentiation by regulating the mRNA expression level of myelin-related genes.
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Williams, Jessica L., Jigisha R. Patel, Brian P. Daniels et Robyn S. Klein. « Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system ». Journal of Experimental Medicine 211, no 5 (14 avril 2014) : 791–99. http://dx.doi.org/10.1084/jem.20131224.
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Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS). Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration. In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown. We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions. CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phospho-S339-CXCR4–specific antibodies and administration of CXCR4 antagonists. These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS.
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Levy, Marion J. F., Beatriz Garcia-Diaz, Frédéric Sedel, Anne Baron-Van Evercooren et Sabah Mozafari. « High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo ». International Journal of Molecular Sciences 23, no 24 (12 décembre 2022) : 15733. http://dx.doi.org/10.3390/ijms232415733.
Texte intégralRésumé :
Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother’s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.
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Zhao, Xianghui, Jiang Wu, Minhua Zheng, Fang Gao et Gong Ju. « Specification and maintenance of oligodendrocyte precursor cells from neural progenitor cells : involvement of microRNA-7a ». Molecular Biology of the Cell 23, no 15 (août 2012) : 2867–77. http://dx.doi.org/10.1091/mbc.e12-04-0270.
Texte intégralRésumé :
The generation of myelinating cells from multipotential neural stem cells in the CNS requires the initiation of specific gene expression programs in oligodendrocytes (OLs). We reasoned that microRNAs (miRNAs) could play an important role in this process by regulating genes crucial for OL development. Here we identified miR-7a as one of the highly enriched miRNAs in oligodendrocyte precursor cells (OPCs), overexpression of which in either neural progenitor cells (NPCs) or embryonic mouse cortex promoted the generation of OL lineage cells. Blocking the function of miR-7a in differentiating NPCs led to a reduction in OL number and an expansion of neuronal populations simultaneously. We also found that overexpression of this miRNA in purified OPC cultures promoted cell proliferation and inhibited further maturation. In addition, miR-7a might exert the effects just mentioned partially by directly repressing proneuronal differentiation factors including Pax6 and NeuroD4, or proOL genes involved in oligodendrocyte maturation. These results suggest that miRNA pathway is essential in determining cell fate commitment for OLs and thus providing a new strategy for modulating this process in OL loss diseases.
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Ktena, Niki, Stefanos Ioannis Kaplanis, Irina Kolotuev, Alexandros Georgilis, Emmanouela Kallergi, Vasiliki Stavroulaki, Vassiliki Nikoletopoulou, Maria Savvaki et Domna Karagogeos. « Autophagic degradation of CNS myelin maintains axon integrity ». Cell Stress 6, no 12 (12 décembre 2022) : 93–107. http://dx.doi.org/10.15698/cst2022.12.274.
Texte intégralRésumé :
(Macro)autophagy is a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation in vitro. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated atg5, a core gene of the autophagic machinery, specifically in myelinating glial cells in vivo by tamoxifen administration (plp-CreERT2; atg5 f/f) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.
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Cammer, Wendy, et Hong Zhang. « Maturation of oligodendrocytes is more sensitive to TNFα than is survival of precursors and immature oligodendrocytes ». Journal of Neuroimmunology 97, no 1-2 (juin 1999) : 37–42. http://dx.doi.org/10.1016/s0165-5728(99)00045-4.
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Davis, Deanna L., Usha Mahawar, Victoria S. Pope, Jeremy Allegood, Carmen Sato-Bigbee et Binks W. Wattenberg. « Dynamics of sphingolipids and the serine palmitoyltransferase complex in rat oligodendrocytes during myelination ». Journal of Lipid Research 61, no 4 (10 février 2020) : 505–22. http://dx.doi.org/10.1194/jlr.ra120000627.
Texte intégralRésumé :
Myelin is a unique lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical myelin components. Yet sphingolipid content and synthesis have not been well characterized in oligodendrocytes, the myelin-producing cells of the CNS. Here, using quantitative real-time PCR, LC-MS/MS-based lipid analysis, and biochemical assays, we examined sphingolipid synthesis during the peak period of myelination in the postnatal rat brain. Importantly, we characterized sphingolipid production in isolated oligodendrocytes. We analyzed sphingolipid distribution and levels of critical enzymes and regulators in the sphingolipid biosynthetic pathway, with focus on the serine palmitoyltransferase (SPT) complex, the rate-limiting step in this pathway. During myelination, levels of the major SPT subunits increased and oligodendrocyte maturation was accompanied by extensive alterations in the composition of the SPT complex. These included changes in the relative levels of two alternative catalytic subunits, SPTLC2 and -3, in the relative levels of isoforms of the small subunits, ssSPTa and -b, and in the isoform distribution of the SPT regulators, the ORMDLs. Myelination progression was accompanied by distinct changes in both the nature of the sphingoid backbone and the N-acyl chains incorporated into sphingolipids. We conclude that the distribution of these changes among sphingolipid family members is indicative of a selective channeling of the ceramide backbone toward specific downstream metabolic pathways during myelination. Our findings provide insights into myelin production in oligodendrocytes and suggest how dysregulation of the biosynthesis of this highly specialized membrane could contribute to demyelinating diseases.
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Yergert, Katie M., Caleb A. Doll, Rebecca O’Rouke, Jacob H. Hines et Bruce Appel. « Identification of 3′ UTR motifs required for mRNA localization to myelin sheaths in vivo ». PLOS Biology 19, no 1 (13 janvier 2021) : e3001053. http://dx.doi.org/10.1371/journal.pbio.3001053.
Texte intégralRésumé :
Myelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth. Purified myelin contains ribosomes and hundreds of mRNAs, supporting a model that mRNA localization and local protein synthesis regulate sheath growth and maturation. However, the mechanisms by which mRNAs are selectively enriched in myelin sheaths are unclear. To investigate how mRNAs are targeted to myelin sheaths, we tested the hypothesis that transcripts are selected for myelin enrichment through consensus sequences in the 3′ untranslated region (3′ UTR). Using methods to visualize mRNA in living zebrafish larvae, we identified candidate 3′ UTRs that were sufficient to localize mRNA to sheaths and enriched near growth zones of nascent membrane. We bioinformatically identified motifs common in 3′ UTRs from 3 myelin-enriched transcripts and determined that these motifs are required and sufficient in a context-dependent manner for mRNA transport to myelin sheaths. Finally, we show that 1 motif is highly enriched in the myelin transcriptome, suggesting that this sequence is a global regulator of mRNA localization during developmental myelination.
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Pla, Laura, Miriam Illa, Carla Loreiro, Mari Carmen Lopez, Paula Vázquez-Aristizabal, Britta Anna Kühne, Marta Barenys, Elisenda Eixarch et Eduard Gratacós. « Structural Brain Changes during the Neonatal Period in a Rabbit Model of Intrauterine Growth Restriction ». Developmental Neuroscience 42, no 5-6 (2020) : 217–29. http://dx.doi.org/10.1159/000512948.
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Background: Intrauterine growth restriction (IUGR) is associated with abnormal neurodevelopment, but the associated structural brain changes are poorly documented. The aim of this study was to describe in an animal model the brain changes at the cellular level in the gray and white matter induced by IUGR during the neonatal period. Methods: The IUGR model was surgically induced in pregnant rabbits by ligating 40–50% of the uteroplacental vessels in 1 horn, whereas the uteroplacental vessels of the contralateral horn were not ligated. After 5 days, IUGR animals from the ligated horn and controls from the nonligated were delivered. On the day of delivery, perinatal data and placentas were collected. On postnatal day 1, functional changes were first evaluated, and thereafter, neuronal arborization in the frontal cortex and density of pre-oligodendrocytes, astrocytes, and microglia in the corpus callosum were evaluated. Results: Higher stillbirth in IUGR fetuses together with a reduced birth weight as compared to controls was evidenced. IUGR animals showed poorer functional results, an altered neuronal arborization pattern, and a decrease in the pre-oligodendrocytes, with no differences in microglia and astrocyte densities. Conclusions: Overall, in the rabbit model used, IUGR is related to functional and brain changes evidenced already at birth, including changes in the neuronal arborization and abnormal oligodendrocyte maturation.
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Marangon, Davide, Marta Boccazzi, Davide Lecca et Marta Fumagalli. « Regulation of Oligodendrocyte Functions : Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair ». Journal of Clinical Medicine 9, no 2 (8 février 2020) : 470. http://dx.doi.org/10.3390/jcm9020470.
Texte intégralRésumé :
Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.
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Lai, Chen, et Linyin Feng. « Implication of γ-secretase in neuregulin-induced maturation of oligodendrocytes ». Biochemical and Biophysical Research Communications 314, no 2 (février 2004) : 535–42. http://dx.doi.org/10.1016/j.bbrc.2003.12.131.
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Othman, Ahmad, David M. Frim, Paul Polak, Snezana Vujicic, Barry G. W. Arnason et Anne I. Boullerne. « Olig1 is expressed in human oligodendrocytes during maturation and regeneration ». Glia 59, no 6 (28 mars 2011) : 914–26. http://dx.doi.org/10.1002/glia.21163.
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Raabe, Florian J., Lenka Slapakova, Moritz J. Rossner, Ludovico Cantuti-Castelvetri, Mikael Simons, Peter G. Falkai et Andrea Schmitt. « Oligodendrocytes as A New Therapeutic Target in Schizophrenia : From Histopathological Findings to Neuron-Oligodendrocyte Interaction ». Cells 8, no 12 (23 novembre 2019) : 1496. http://dx.doi.org/10.3390/cells8121496.
Texte intégralRésumé :
Imaging and postmortem studies have revealed disturbed oligodendroglia-related processes in patients with schizophrenia and provided much evidence for disturbed myelination, irregular gene expression, and altered numbers of oligodendrocytes in the brains of schizophrenia patients. Oligodendrocyte deficits in schizophrenia might be a result of failed maturation and disturbed regeneration and may underlie the cognitive deficits of the disease, which are strongly associated with impaired long-term outcome. Cognition depends on the coordinated activity of neurons and interneurons and intact connectivity. Oligodendrocyte precursors form a synaptic network with parvalbuminergic interneurons, and disturbed crosstalk between these cells may be a cellular basis of pathology in schizophrenia. However, very little is known about the exact axon-glial cellular and molecular processes that may be disturbed in schizophrenia. Until now, investigations were restricted to peripheral tissues, such as blood, correlative imaging studies, genetics, and molecular and histological analyses of postmortem brain samples. The advent of human-induced pluripotent stem cells (hiPSCs) will enable functional analysis in patient-derived living cells and holds great potential for understanding the molecular mechanisms of disturbed oligodendroglial function in schizophrenia. Targeting such mechanisms may contribute to new treatment strategies for previously treatment-resistant cognitive symptoms.
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Jacobs, Erin C., Samuel D. Reyes, Celia W. Campagnoni, M. Irene Givogri, Kathy Kampf, Vance Handley, Vilma Spreuer, Robin Fisher, Wendy Macklin et Anthony T. Campagnoni. « Targeted Overexpression of a Golli-Myelin Basic Protein Isoform to Oligodendrocytes Results in Aberrant Oligodendrocyte Maturation and Myelination ». ASN Neuro 1, no 4 (23 septembre 2009) : AN20090029. http://dx.doi.org/10.1042/an20090029.
Texte intégralRésumé :
Recently, several in vitro studies have shown that the golli-myelin basic proteins regulate Ca2+ homoeostasis in OPCs (oligodendrocyte precursor cells) and immature OLs (oligodendrocytes), and that a number of the functions of these cells are affected by cellular levels of the golli proteins. To determine the influence of golli in vivo on OL development and myelination, a transgenic mouse was generated in which the golli isoform J37 was overexpressed specifically within OLs and OPCs. The mouse, called JOE (J37-overexpressing), is severely hypomyelinated between birth and postnatal day 50. During this time, it exhibits severe intention tremors that gradually abate at later ages. After postnatal day 50, ultrastructural studies and Northern and Western blot analyses indicate that myelin accumulates in the brain, but never reaches normal levels. Several factors appear to underlie the extensive hypomyelination. In vitro and in vivo experiments indicate that golli overexpression causes a significant delay in OL maturation, with accumulation of significantly greater numbers of pre-myelinating OLs that fail to myelinate axons during the normal myelinating period. Immunohistochemical studies with cell death and myelin markers indicate that JOE OLs undergo a heightened and extended period of cell death and are unable to effectively myelinate until 2 months after birth. The results indicate that increased levels of golli in OPC/OLs delays myelination, causing significant cell death of OLs particularly in white matter tracts. The results provide in vivo evidence for a significant role of the golli proteins in the regulation of maturation of OLs and normal myelination.
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Tang, Dean G., Yasuhito M. Tokumoto et Martin C. Raff. « Long-Term Culture of Purified Postnatal Oligodendrocyte Precursor Cells ». Journal of Cell Biology 148, no 5 (6 mars 2000) : 971–84. http://dx.doi.org/10.1083/jcb.148.5.971.
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Oligodendrocytes myelinate axons in the vertebrate central nervous system (CNS). They develop from precursor cells (OPCs), some of which persist in the adult CNS. Adult OPCs differ in many of their properties from OPCs in the developing CNS. In this study we have purified OPCs from postnatal rat optic nerve and cultured them in serum-free medium containing platelet-derived growth factor (PDGF), the main mitogen for OPCs, but in the absence of thyroid hormone in order to inhibit their differentiation into oligodendrocytes. We find that many of the cells continue to proliferate for more than a year and progressively acquire a number of the characteristics of OPCs isolated from adult optic nerve. These findings suggest that OPCs have an intrinsic maturation program that progressively changes the cell's phenotype over many months. When we culture the postnatal OPCs in the same conditions but with the addition of basic fibroblast growth factor (bFGF), the cells acquire these mature characteristics much more slowly, suggesting that the combination of bFGF and PDGF, previously shown to inhibit OPC differentiation, also inhibits OPC maturation. The challenge now is to determine the molecular basis of such a protracted maturation program and how the program is restrained by bFGF.
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Muñoz-Esquivel, Jonathan, Peter Göttle, Lucinda Aguirre-Cruz, José Flores-Rivera, Teresa Corona, Gustavo Reyes-Terán, Patrick Küry et Klintsy J. Torres. « Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells ». ASN Neuro 11 (janvier 2019) : 175909141983244. http://dx.doi.org/10.1177/1759091419832444.
Texte intégralRésumé :
Phosphodiesterases (PDEs) have previously been implicated in oligodendrocyte maturation and myelination of central nervous system axons. Sildenafil citrate is a phosphodiesterase inhibitor known to block PDE5, which also reduces inflammation in the experimental autoimmune encephalomyelitis demyelinating model. To find out whether this inhibitor might exert beneficial effects on central nervous system myelin repair activities, we investigated to what degree sildenafil modulates differentiation and maturation of cultured primary rat oligodendroglial precursor cells (OPCs). To this end, gene and protein expression of 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, myelin basic protein, and myelin oligodendrocyte glycoprotein, as well as of negative regulators of myelin expression (Hes1, Hes5, Id2, Id4, Rock2, and p57Kip2) were measured in OPCs treated with sildenafil. Moreover, the subcellular distribution of the p57kip2 protein was determined after sildenafil treatment, as this revealed to be an early predictor of the oligodendroglial differentiation capacity. In vitro myelination assays were done to measure the myelination capacity of oligodendrocytes treated with sildenafil. We found that sildenafil significantly diminished myelin gene expression and protein expression. Moreover, sildenafil also increased the expression of Id2 and Id4 negative transcriptional regulators, and the degree of OPCs with cytoplasmic p57kip2 protein localization was reduced, providing evidence that the PDE blocker impaired the differentiation capacity. Finally, sildenafil also interfered with the establishment of internodes as revealed by in vitro myelination assays. We therefore conclude that blocking PDE5 activities exerts a negative impact on intrinsic oligodendroglial differentiation processes.