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Wright JL, Jiang Y, Nayar SG, Li H, Richardson WD. The INO80 Chromatin Remodeling Complex Regulates Histone H2A.Z Mobility and the G1-S Transition in Oligodendrocyte Precursors. Glia 2025; 73:1307-1323. [PMID: 40017313 PMCID: PMC12012327 DOI: 10.1002/glia.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 02/11/2025] [Accepted: 02/18/2025] [Indexed: 03/01/2025]
Abstract
Chromatin remodeling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival, and maintenance. We asked whether CRCs also control the proliferation of OL precursors (OPs)-focusing on the INO80 complex, which is known to regulate the proliferation of a variety of other cell types during development and disease. CRISPR/Cas9-mediated inactivation of Ino80 in vitro, or Cre-mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80-deficient mice, but correlated RNAseq and ATAC-seq uncovered no general correlation between gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following the loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.
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Affiliation(s)
- Jordan L. Wright
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Yi Jiang
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Stuart G. Nayar
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
| | - Huiliang Li
- Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
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Genc S, Ball G, Chamberland M, Raven EP, Tax CMW, Ward I, Yang JYM, Palombo M, Jones DK. MRI signatures of cortical microstructure in human development align with oligodendrocyte cell-type expression. Nat Commun 2025; 16:3317. [PMID: 40195348 PMCID: PMC11977195 DOI: 10.1038/s41467-025-58604-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 03/27/2025] [Indexed: 04/09/2025] Open
Abstract
Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss. Recent advances in MRI hardware and biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. Using ultra-strong gradient MRI, this study quantifies cortical neurite and soma microstructure in typically developing youth. Across domain-specific networks, cortical neurite signal fraction, attributed to neuronal and glial processes, increases with age. The apparent soma radius, attributed to the apparent radius of glial and neuronal cell bodies, decreases with age. Analyses of two independent post-mortem datasets reveal that genes increasing in expression through adolescence are significantly enriched in cortical oligodendrocytes and Layer 5-6 neurons. In our study, we show spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes, suggesting that ongoing cortical myelination processes drive adolescent cortical development.
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Affiliation(s)
- Sila Genc
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK.
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, VIC, Australia.
- Neuroscience Advanced Clinical Imaging Service (NACIS), Department of Neurosurgery, The Royal Children's Hospital, Parkville, VIC, Australia.
| | - Gareth Ball
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, VIC, Australia
- Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
| | - Maxime Chamberland
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
- Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Erika P Raven
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
- Department of Radiology, NYU Grossman School of Medicine, New York, NY, USA
- Institute for Translational Neuroscience, NYU Grossman School of Medicine, New York, NY, USA
| | - Chantal M W Tax
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
- Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Isobel Ward
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Joseph Y M Yang
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, VIC, Australia
- Neuroscience Advanced Clinical Imaging Service (NACIS), Department of Neurosurgery, The Royal Children's Hospital, Parkville, VIC, Australia
- Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
- Neuroscience Research, Clinical Sciences, Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Marco Palombo
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
- School of Computer Science and Informatics, Cardiff University, Cardiff, UK
| | - Derek K Jones
- Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK
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Falcón P, Brito Á, Escandón M, Roa JF, Martínez NW, Tapia-Godoy A, Farfán P, Matus S. GCN2-Mediated eIF2α Phosphorylation Is Required for Central Nervous System Remyelination. Int J Mol Sci 2025; 26:1626. [PMID: 40004088 PMCID: PMC11855834 DOI: 10.3390/ijms26041626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Under conditions of amino acid deficiency, mammalian cells activate a nutrient-sensing kinase known as general control nonderepressible 2 (GCN2). The activation of GCN2 results in the phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α), which can be phosphorylated by three other three integrated stress response (ISR) kinases, reducing overall protein synthesis. GCN2 activation also promotes the translation of specific mRNAs, some of which encode transcription factors that enhance the transcription of genes involved in the synthesis, transport, and metabolism of amino acids to restore cellular homeostasis. The phosphorylation of eIF2α has been shown to protect oligodendrocytes, the cells responsible for producing myelin in the central nervous system during remyelination. Here, we explore the potential role of the kinase GCN2 in the myelination process. We challenged mice deficient in the GCN2-encoding gene with a pharmacological demyelinating stimulus (cuprizone) and evaluated the recovery of myelin as well as ISR activation through the levels of eIF2α phosphorylation. Our findings indicate that GCN2 controls the establishment of myelin by fine-tuning its abundance and morphology in the central nervous system. We also found that GCN2 is essential for remyelination. Surprisingly, we discovered that GCN2 is necessary to maintain eIF2α levels during remyelination.
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Affiliation(s)
- Paulina Falcón
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
| | - Álvaro Brito
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
| | - Marcela Escandón
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Ph.D. “Program in Cell Biology and Biomedicine”, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
| | - Juan Francisco Roa
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Ph.D. “Program in Cell Biology and Biomedicine”, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
| | - Nicolas W. Martínez
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580704, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
| | - Ariel Tapia-Godoy
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580704, Chile
| | - Pamela Farfán
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580704, Chile
| | - Soledad Matus
- Fundación Ciencia & Vida, Avenida del Valle 725, Huechuraba, Santiago 8580704, Chile; (P.F.); (Á.B.); (M.E.); (J.F.R.); (N.W.M.); (A.T.-G.); (P.F.)
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580704, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
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Hentze J, Folke J, Aznar S, Nyeng P, Brudek T, Hansen C. DNAJB6 is expressed in neurons and oligodendrocytes of the human brain. Glia 2024; 72:2313-2326. [PMID: 39228066 DOI: 10.1002/glia.24615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024]
Abstract
DNAJB6 is a suppressor of α-synuclein aggregation in vivo and in vitro. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed post-mortem normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%-53%) of the oligodendrocyte population and in the majority (68%-80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.
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Affiliation(s)
- Jónvá Hentze
- Centre for Neuroscience and Stereology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Jonas Folke
- Centre for Neuroscience and Stereology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
- Copenhagen Centre for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Susana Aznar
- Centre for Neuroscience and Stereology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
- Copenhagen Centre for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Pia Nyeng
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Tomasz Brudek
- Centre for Neuroscience and Stereology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
- Copenhagen Centre for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Christian Hansen
- Department of Technology, University College Copenhagen, Copenhagen, Denmark
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Genc S, Ball G, Chamberland M, Raven EP, Tax CM, Ward I, Yang JYM, Palombo M, Jones DK. MRI signatures of cortical microstructure in human development align with oligodendrocyte cell-type expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.30.605934. [PMID: 39131383 PMCID: PMC11312524 DOI: 10.1101/2024.07.30.605934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss with age. However, the underlying cellular mechanisms remain elusive with conventional neuroimaging. Recent advances in MRI hardware and new biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. This study used ultra-strong gradient MRI to obtain high-resolution, in vivo estimates of cortical neurite and soma microstructure in sample of typically developing children and adolescents. Cortical neurite signal fraction, attributed to neuronal and glial processes, increased with age (mean R2 fneurite=.53, p<3.3e-11, 11.91% increase over age), while apparent soma radius decreased (mean R2 Rsoma=.48, p<4.4e-10, 1% decrease over age) across domain-specific networks. To complement these findings, developmental patterns of cortical gene expression in two independent post-mortem databases were analysed. This revealed increased expression of genes expressed in oligodendrocytes, and excitatory neurons, alongside a relative decrease in expression of genes expressed in astrocyte, microglia and endothelial cell-types. Age-related genes were significantly enriched in cortical oligodendrocytes, oligodendrocyte progenitors and Layer 5-6 neurons (pFDR<.001) and prominently expressed in adolescence and young adulthood. The spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes suggest that ongoing cortical myelination processes contribute to adolescent cortical development. These findings highlight the role of intra-cortical myelination in cortical maturation during adolescence and into adulthood.
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Affiliation(s)
- Sila Genc
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Neuroscience Advanced Clinical Imaging Service (NACIS), Department of Neurosurgery, The Royal Children's Hospital, Parkville, Victoria, Australia
| | - Gareth Ball
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Maxime Chamberland
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
- Eindhoven University of Technology, Department of Mathematics and Computer Science, Eindhoven, The Netherlands
| | - Erika P Raven
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, USA
| | - Chantal Mw Tax
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
- Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Isobel Ward
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
- Data and Analysis for Social Care and Health, Office for National Statistics, Newport, United Kingdom
| | - Joseph Yuan-Mou Yang
- Developmental Imaging, Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia
- Neuroscience Advanced Clinical Imaging Service (NACIS), Department of Neurosurgery, The Royal Children's Hospital, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Marco Palombo
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
| | - Derek K Jones
- Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom
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Barbaresi P, Fabri M, Lorenzi T, Sagrati A, Morroni M. Intrinsic organization of the corpus callosum. Front Physiol 2024; 15:1393000. [PMID: 39035452 PMCID: PMC11259024 DOI: 10.3389/fphys.2024.1393000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/16/2024] [Indexed: 07/23/2024] Open
Abstract
The corpus callosum-the largest commissural fiber system connecting the two cerebral hemispheres-is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons.
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Affiliation(s)
- Paolo Barbaresi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Mara Fabri
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Teresa Lorenzi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Andrea Sagrati
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Manrico Morroni
- Electron Microscopy Unit, Azienda Ospedaliero-Universitaria, Ancona, Italy
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Franklin RJM, Bodini B, Goldman SA. Remyelination in the Central Nervous System. Cold Spring Harb Perspect Biol 2024; 16:a041371. [PMID: 38316552 PMCID: PMC10910446 DOI: 10.1101/cshperspect.a041371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, while this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granule neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this work, we will (1) review the biology of remyelination, including the cells and signals involved; (2) describe when remyelination occurs and when and why it fails, including the consequences of its failure; and (3) discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain.
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Affiliation(s)
- Robin J M Franklin
- Altos Labs Cambridge Institute of Science, Cambridge CB21 6GH, United Kingdom
| | - Benedetta Bodini
- Sorbonne Université, Paris Brain Institute, CNRS, INSERM, Paris 75013, France
- Saint-Antoine Hospital, APHP, Paris 75012, France
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA
- University of Copenhagen Faculty of Medicine, Copenhagen 2200, Denmark
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Zhang J, Li W, Yue Q, Liu L, Hou ST, Ju J. Rapamycin Exerts an Antidepressant Effect and Enhances Myelination in the Prefrontal Cortex of Chronic Restraint Stress Mice. Neuroscience 2023; 535:99-107. [PMID: 37926147 DOI: 10.1016/j.neuroscience.2023.10.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
Depressive disorder is a psychiatric condition that is characterized by the core symptoms of anhedonia and learned helplessness. Myelination loss was recently found in the prefrontal cortex (PFC) of patients with depression and animal models, but the mechanism of this loss is unclear. In our previous study, chronic restraint stress (CRS) mice showed depressive-like symptoms. In this study, we found that myelin was reduced in the PFC of CRS mice. We also observed increased mammalian target of rapamycin (mTOR) phosphorylation levels in the PFC. Chronic injections of rapamycin, a mTOR complex inhibitor, prevented depressive behavior as shown by the forced swimming test and sucrose preference test. Rapamycin also increased myelination in the PFC of CRS mice. In summary, we found that CRS enhanced mTOR signaling and reduced myelination in the PFC and that rapamycin could prevent it. Our study provides the etiology of reduced myelin in depressive symptoms and suggests that mTOR signaling could be a target for treating depression or improving myelination deficits in depressive disorders.
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Affiliation(s)
- Jin Zhang
- School of Basic Medical Sciences, Xi'an Medical University, Xi'an, China; State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Shenzhen Graduate School, Peking University, Shenzhen, China
| | - Weifen Li
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Shenzhen Graduate School, Peking University, Shenzhen, China
| | - Qi Yue
- Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, China; Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Luping Liu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Special Administrative Region
| | - Sheng-Tao Hou
- Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, China.
| | - Jun Ju
- Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, China.
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Gutierrez BA, González-Coronel JM, Arellano RO, Limon A. Transcriptional and bioinformatic analysis of GABA A receptors expressed in oligodendrocyte progenitor cells from the human brain. Front Mol Neurosci 2023; 16:1279232. [PMID: 37953877 PMCID: PMC10637375 DOI: 10.3389/fnmol.2023.1279232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/12/2023] [Indexed: 11/14/2023] Open
Abstract
Introduction Oligodendrocyte progenitor cells (OPCs) are vital for neuronal myelination and remyelination in the central nervous system. While the molecular mechanisms involved in OPCs' differentiation and maturation are not completely understood, GABA is known to positively influence these processes through the activation of GABAA receptors (GABAARs). The molecular identity of GABAARs expressed in human OPCs remains unknown, which restricts their specific pharmacological modulation to directly assess their role in oligodendrocytes' maturation and remyelination. Methods In this study, we conducted a transcriptomic analysis to investigate the molecular stoichiometry of GABAARs in OPCs from the human brain. Using eight available transcriptomic datasets from the human brain cortex of control individuals, we analyzed the mRNA expression of all 19 known GABAARs subunit genes in OPCs, with variations observed across different ages. Results Our analysis indicated that the most expressed subunits in OPCs are α1-3, β1-3, γ1-3, and ε. Moreover, we determined that the combination of any α with β2 and γ2 is likely to form heteropentameric GABAARs in OPCs. Importantly, we also found a strong correlation between GABAAR subunits and transcripts for postsynaptic scaffold proteins, suggesting the potential postsynaptic clustering of GABAARs in OPCs. Discussion This study presents the first transcriptional-level identification of GABAAR subunits expressed in human OPCs, providing potential receptor combinations. Understanding the molecular composition of GABAARs in OPCs not only enhances our knowledge of the underlying mechanisms in oligodendrocyte maturation but also opens avenues for targeted pharmacological interventions aimed at modulating these receptors to promote remyelination in neurological disorders.
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Affiliation(s)
- Berenice A. Gutierrez
- Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, United States
- Laboratorio de Neurofisiología Celular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Mexico
| | - José Manuel González-Coronel
- Laboratorio de Neurofisiología Celular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Mexico
| | - Rogelio O. Arellano
- Laboratorio de Neurofisiología Celular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Mexico
| | - Agenor Limon
- Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, United States
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Xiao Y, Czopka T. Myelination-independent functions of oligodendrocyte precursor cells in health and disease. Nat Neurosci 2023; 26:1663-1669. [PMID: 37653126 DOI: 10.1038/s41593-023-01423-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/27/2023] [Indexed: 09/02/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) are a population of tissue-resident glial cells found throughout the CNS, constituting approximately 5% of all CNS cells and persisting from development to adulthood and aging. The canonical role of OPCs is to give rise to myelinating oligodendrocytes. However, additional functions of OPCs beyond this traditional role as precursors have been suggested for a long time. In this Perspective, we provide an overview of the multiple myelination-independent functions that have been described for OPCs in the context of neuron development, angiogenesis, inflammatory response, axon regeneration and their recently discovered roles in neural circuit remodeling.
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Affiliation(s)
- Yan Xiao
- Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany
| | - Tim Czopka
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
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Shumilov K, Xiao S, Ni A, Celorrio M, Friess SH. Recombinant Erythropoietin Induces Oligodendrocyte Progenitor Cell Proliferation After Traumatic Brain Injury and Delayed Hypoxemia. Neurotherapeutics 2023; 20:1859-1874. [PMID: 37768487 PMCID: PMC10684442 DOI: 10.1007/s13311-023-01443-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Traumatic brain injury (TBI) can result in axonal loss and demyelination, leading to persistent damage in the white matter. Demyelinated axons are vulnerable to pathologies related to an abnormal myelin structure that expose neurons to further damage. Oligodendrocyte progenitor cells (OPCs) mediate remyelination after recruitment to the injury site. Often this process is inefficient due to inadequate OPC proliferation. To date, no effective treatments are currently available to stimulate OPC proliferation in TBI. Recombinant human erythropoietin (rhEPO) is a pleiotropic neuroprotective cytokine, and its receptor is present in all stages of oligodendroglial lineage cell differentiation. Therefore, we hypothesized that rhEPO administration would enhance remyelination after TBI through the modulation of OPC response. Utilizing a murine model of controlled cortical impact and a primary OPC culture in vitro model, we characterized the impact of rhEPO on remyelination and proliferation of oligodendrocyte lineage cells. Myelin black gold II staining of the peri-contusional corpus callosum revealed an increase in myelinated area in association with an increase in BrdU-positive oligodendrocytes in injured mice treated with rhEPO. Furthermore, morphological analysis of OPCs showed a decrease in process length in rhEPO-treated animals. RhEPO treatment increased OPC proliferation after in vitro CSPG exposure. Erythropoietin receptor (EPOr) gene knockdown using siRNA prevented rhEPO-induced OPC proliferation, demonstrating that the rhEPO effect on OPC response is EPOr activation dependent. Together, our findings demonstrate that rhEPO administration may promote myelination by increasing oligodendrocyte lineage cell proliferation after TBI.
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Affiliation(s)
- Kirill Shumilov
- Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, One Children's Place, St. Louis, MO, 63110, USA
| | - Sophia Xiao
- Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, One Children's Place, St. Louis, MO, 63110, USA
| | - Allen Ni
- Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, One Children's Place, St. Louis, MO, 63110, USA
| | - Marta Celorrio
- Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, One Children's Place, St. Louis, MO, 63110, USA
| | - Stuart H Friess
- Department of Pediatrics, Washington University in St. Louis School of Medicine, Campus Box 8208, One Children's Place, St. Louis, MO, 63110, USA.
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12
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Bazarek SF, Thaqi M, King P, Mehta AR, Patel R, Briggs CA, Reisenbigler E, Yousey JE, Miller EA, Stutzmann GE, Marr RA, Peterson DA. Engineered neurogenesis in naïve adult rat cortex by Ngn2-mediated neuronal reprogramming of resident oligodendrocyte progenitor cells. Front Neurosci 2023; 17:1237176. [PMID: 37662111 PMCID: PMC10471311 DOI: 10.3389/fnins.2023.1237176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
Adult tissue stem cells contribute to tissue homeostasis and repair but the long-lived neurons in the human adult cerebral cortex are not replaced, despite evidence for a limited regenerative response. However, the adult cortex contains a population of proliferating oligodendrocyte progenitor cells (OPCs). We examined the capacity of rat cortical OPCs to be re-specified to a neuronal lineage both in vitro and in vivo. Expressing the developmental transcription factor Neurogenin2 (Ngn2) in OPCs isolated from adult rat cortex resulted in their expression of early neuronal lineage markers and genes while downregulating expression of OPC markers and genes. Ngn2 induced progression through a neuronal lineage to express mature neuronal markers and functional activity as glutamatergic neurons. In vivo retroviral gene delivery of Ngn2 to naive adult rat cortex ensured restricted targeting to proliferating OPCs. Ngn2 expression in OPCs resulted in their lineage re-specification and transition through an immature neuronal morphology into mature pyramidal cortical neurons with spiny dendrites, axons, synaptic contacts, and subtype specification matching local cytoarchitecture. Lineage re-specification of rat cortical OPCs occurred without prior injury, demonstrating these glial progenitor cells need not be put into a reactive state to achieve lineage reprogramming. These results show it may be feasible to precisely engineer additional neurons directly in adult cerebral cortex for experimental study or potentially for therapeutic use to modify dysfunctional or damaged circuitry.
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Affiliation(s)
- Stanley F. Bazarek
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Mentor Thaqi
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Patrick King
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Amol R. Mehta
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Ronil Patel
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Clark A. Briggs
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Emily Reisenbigler
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Jonathon E. Yousey
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Elis A. Miller
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Grace E. Stutzmann
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Robert A. Marr
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Daniel A. Peterson
- Center for Stem Cell and Regenerative Medicine, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
- Center for Neurodegenerative Disease and Therapeutics, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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13
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Liu Y, Shen X, Zhang Y, Zheng X, Cepeda C, Wang Y, Duan S, Tong X. Interactions of glial cells with neuronal synapses, from astrocytes to microglia and oligodendrocyte lineage cells. Glia 2023; 71:1383-1401. [PMID: 36799296 DOI: 10.1002/glia.24343] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/06/2023] [Accepted: 01/08/2023] [Indexed: 02/18/2023]
Abstract
The mammalian brain is a complex organ comprising neurons, glia, and more than 1 × 1014 synapses. Neurons are a heterogeneous group of electrically active cells, which form the framework of the complex circuitry of the brain. However, glial cells, which are primarily divided into astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte precursor cells (OPCs), constitute approximately half of all neural cells in the mammalian central nervous system (CNS) and mainly provide nutrition and tropic support to neurons in the brain. In the last two decades, the concept of "tripartite synapses" has drawn great attention, which emphasizes that astrocytes are an integral part of the synapse and regulate neuronal activity in a feedback manner after receiving neuronal signals. Since then, synaptic modulation by glial cells has been extensively studied and substantially revised. In this review, we summarize the latest significant findings on how glial cells, in particular, microglia and OL lineage cells, impact and remodel the structure and function of synapses in the brain. Our review highlights the cellular and molecular aspects of neuron-glia crosstalk and provides additional information on how aberrant synaptic communication between neurons and glia may contribute to neural pathologies.
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Affiliation(s)
- Yao Liu
- Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Shen
- Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhan Zhang
- College of Basic Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoli Zheng
- Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Carlos Cepeda
- Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Yao Wang
- Department of Assisted Reproduction, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shumin Duan
- Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China
| | - Xiaoping Tong
- Songjiang Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
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14
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Selcen I, Prentice E, Casaccia P. The epigenetic landscape of oligodendrocyte lineage cells. Ann N Y Acad Sci 2023; 1522:24-41. [PMID: 36740586 PMCID: PMC10085863 DOI: 10.1111/nyas.14959] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The epigenetic landscape of oligodendrocyte lineage cells refers to the cell-specific modifications of DNA, chromatin, and RNA that define a unique gene expression pattern of functionally specialized cells. Here, we focus on the epigenetic changes occurring as progenitors differentiate into myelin-forming cells and respond to the local environment. First, modifications of DNA, RNA, nucleosomal histones, key principles of chromatin organization, topologically associating domains, and local remodeling will be reviewed. Then, the relationship between epigenetic modulators and RNA processing will be explored. Finally, the reciprocal relationship between the epigenome as a determinant of the mechanical properties of cell nuclei and the target of mechanotransduction will be discussed. The overall goal is to provide an interpretative key on how epigenetic changes may account for the heterogeneity of the transcriptional profiles identified in this lineage.
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Affiliation(s)
- Ipek Selcen
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York, USA.,Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA
| | - Emily Prentice
- Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA.,Graduate Program in Biology, The Graduate Center of The City University of New York, New York, New York, USA
| | - Patrizia Casaccia
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York, USA.,Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA.,Graduate Program in Biology, The Graduate Center of The City University of New York, New York, New York, USA
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15
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Steliga A, Lietzau G, Wójcik S, Kowiański P. Transient cerebral ischemia induces the neuroglial proliferative activity and the potential to redirect neuroglial differentiation. J Chem Neuroanat 2023; 127:102192. [PMID: 36403746 DOI: 10.1016/j.jchemneu.2022.102192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 10/31/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022]
Abstract
Brain injury triggers a complex response involving morphological changes, cellular proliferation, and differentiation of newly formed neuroglial subpopulations. These processes have been extensively studied in animal stroke models with permanent large vessel occlusion. However, less is known about neuroglial response after transient cerebral ischemia. Herein, we aimed to determine an astrocytic and NG2 glial proliferative response, potential changes in expression of developmental neuroglial markers: vimentin, nestin, oligodendrocyte transcription marker (Olig2), and a role of neuroglial subpopulations as a source of cells replenishing structural deficiencies in the ischemic brain. Results showed an induction of a proliferative neuroglial response in the peri-infarct area reflected in an increased percentage of GFAP/Ki67 + and NG2/Ki67 + cells within 4 weeks after transient MCAO. The peak of GFAP+ astrocytes proliferation of 30.3 ± 10.3% was observed in the first week, and a peak of NG2 + cells proliferation of 23.1 ± 11.8% in the second week after stroke. The presence of GFAP/Vimentin+ and GFAP/Nestin+ cells, as well as GFAP/Olig2 + and NG2/Olig2 + cells indicated an induction of developmental phenotypes with a differentiation potential. Finally, observed between day 1 and week 3 transient GFAP/NG2 + colocalization suggests the heterogeneous source of the reactive neuroglia after transient MCAO. Altogether, one-hour MCAO is a sufficient pathological stimulus to trigger a strong proliferative response of GFAP+ and NG2 + neuroglial cells and induce their early developmental phenotype. Our results suggest that transient ischemia may initiate a change in the direction of differentiation within the neuroglia cell population.
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Affiliation(s)
- Aleksandra Steliga
- Institute of Health Sciences, Pomeranian University in Słupsk, Bohaterów Westerplatte 64, 76-200 Słupsk, Poland
| | - Grazyna Lietzau
- Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland.
| | - Sławomir Wójcik
- Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Przemysław Kowiański
- Institute of Health Sciences, Pomeranian University in Słupsk, Bohaterów Westerplatte 64, 76-200 Słupsk, Poland; Division of Anatomy and Neurobiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland.
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16
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Ribeiro M, Ayupe AC, Beckedorff FC, Levay K, Rodriguez S, Tsoulfas P, Lee JK, Nascimento-Dos-Santos G, Park KK. Retinal ganglion cell expression of cytokine enhances occupancy of NG2 cell-derived astrocytes at the nerve injury site: Implication for axon regeneration. Exp Neurol 2022; 355:114147. [PMID: 35738417 PMCID: PMC10648309 DOI: 10.1016/j.expneurol.2022.114147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/27/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
Following injury in the central nervous system, a population of astrocytes occupy the lesion site, form glial bridges and facilitate axon regeneration. These astrocytes originate primarily from resident astrocytes or NG2+ oligodendrocyte progenitor cells. However, the extent to which these cell types give rise to the lesion-filling astrocytes, and whether the astrocytes derived from different cell types contribute similarly to optic nerve regeneration remain unclear. Here we examine the distribution of astrocytes and NG2+ cells in an optic nerve crush model. We show that optic nerve astrocytes partially fill the injury site over time after a crush injury. Viral mediated expression of a growth-promoting factor, ciliary neurotrophic factor (CNTF), in retinal ganglion cells (RGCs) promotes axon regeneration without altering the lesion size or the degree of lesion-filling GFAP+ cells. Strikingly, using inducible NG2CreER driver mice, we found that CNTF overexpression in RGCs increases the occupancy of NG2+ cell-derived astrocytes in the optic nerve lesion. An EdU pulse-chase experiment shows that the increase in NG2 cell-derived astrocytes is not due to an increase in cell proliferation. Lastly, we performed RNA-sequencing on the injured optic nerve and reveal that CNTF overexpression in RGCs results in significant changes in the expression of distinct genes, including those that encode chemokines, growth factor receptors, and immune cell modulators. Even though CNTF-induced axon regeneration has long been recognized, this is the first evidence of this procedure affecting glial cell fate at the optic nerve crush site. We discuss possible implication of these results for axon regeneration.
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Affiliation(s)
- Marcio Ribeiro
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA; Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, AA7103 MCN/VUIIS, 1161 21st Ave. S., Nashville, TN 37232, USA
| | - Ana C Ayupe
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Felipe C Beckedorff
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, University of Miami Miller School of Medicine, Room 715, 1501 NW 10th Avenue, Miami, FL 33136, USA
| | - Konstantin Levay
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Sara Rodriguez
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Pantelis Tsoulfas
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Jae K Lee
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Gabriel Nascimento-Dos-Santos
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Kevin K Park
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
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17
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The 5-HT and PLC Signaling Pathways Regulate the Secretion of IL-1β, TNF-α and BDNF from NG2 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7425538. [PMID: 35600957 PMCID: PMC9122684 DOI: 10.1155/2022/7425538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 01/26/2023]
Abstract
The present study was clarified the relationship between NG2 glial cells and 5-hydroxytryptamine (5-HT) to further revealed a role in the regulation of cortical excitability. The co-localization of NG2 cells and 5-HT in rat prefrontal cortex was determined using immunofluorescence. Different concentrations of 5-HT were applied to cultured NG2 cells. Real-time PCR measured the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF). Changes in the expression of IL-1β, TNF-α, and BDNF in NG2 cells were detected after the addition of 5-HT receptor specific blockers and phospholipase C (PLC) specific activators and inhibitors. The results confirmed that the NG2 protein and 5-HT co-localized in the prefrontal cortex. 5-HT treatment of NG2 cells significantly reduced the expression of IL-1β and BDNF mRNA and increased the expression of TNF-α. The 5-HT receptor specific inhibitors alverine citrate, ketanserin, ondansetron and SB-399885 blocked the regulatory effects of 5-HT on NG2 cells. The PLC signal was linked to the secretion of IL-1β, TNF-α and BDNF in NG2 cells. These results indicated that 5-HT affected IL-1β, TNF-α, and BDNF secretion from NG2 cells via the 5-HT1A, 5-HT2A, 5-HT3, 5-HT6 receptors and the PLC signaling pathway.
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18
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Sánchez-González R, López-Mascaraque L. Lineage Relationships Between Subpallial Progenitors and Glial Cells in the Piriform Cortex. Front Neurosci 2022; 16:825969. [PMID: 35386594 PMCID: PMC8979001 DOI: 10.3389/fnins.2022.825969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/21/2022] [Indexed: 11/22/2022] Open
Abstract
The piriform cortex is a paleocortical area, located in the ventrolateral surface of the rodent forebrain, receiving direct input from the olfactory bulb. The three layers of the PC are defined by the diversity of glial and neuronal cells, marker expression, connections, and functions. However, the glial layering, ontogeny, and sibling cell relationship along the PC is an unresolved question in the field. Here, using multi-color genetic lineage tracing approaches with different StarTrack strategies, we performed a rigorous analysis of the derived cell progenies from progenitors located at the subpallium ventricular surface. First, we specifically targeted E12-progenitors with UbC-StarTrack to analyze their adult derived-cell progeny and their location within the piriform cortex layers. The vast majority of the cell progeny derived from targeted progenitors were identified as neurons, but also astrocytes and NG2 cells. Further, to specifically target single Gsx-2 subpallial progenitors and their derived cell-progeny in the piriform cortex, we used the UbC-(Gsx-2-hyPB)-StarTrack to perform an accurate analysis of their clonal relationships. Our results quantitatively delineate the adult clonal cell pattern from single subpallial E12-progenitors, focusing on glial cells. In summary, there is a temporal pattern in the assembly of the glial cell diversity in the piriform cortex, which also reveals spatio-temporal progenitor heterogeneity.
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19
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Sunkaria A, Bhardwaj S. Sleep Disturbance and Alzheimer's Disease: The Glial Connection. Neurochem Res 2022; 47:1799-1815. [PMID: 35303225 DOI: 10.1007/s11064-022-03578-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/27/2022] [Accepted: 03/09/2022] [Indexed: 12/28/2022]
Abstract
Poor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer's patients. Glial cells have long been implicated in the progression of Alzheimer's disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep-wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer's or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis. Role of glia in sleep disturbance and Alzheimer's progression.
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Affiliation(s)
- Aditya Sunkaria
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
| | - Supriya Bhardwaj
- Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
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20
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Liu Z, Yan M, Lei W, Jiang R, Dai W, Chen J, Wang C, Li L, Wu M, Nian X, Li D, Sun D, Lv X, Wang C, Xie C, Yao L, Wu C, Hu J, Xiao N, Mo W, Wang Z, Zhang L. Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling. J Clin Invest 2022; 132:155096. [PMID: 35143418 PMCID: PMC8970680 DOI: 10.1172/jci155096] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.
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Affiliation(s)
- Zhixiong Liu
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Minbiao Yan
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Wanying Lei
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Rencai Jiang
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Wenxiu Dai
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Jialin Chen
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Chaomeng Wang
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Li Li
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Mei Wu
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Ximing Nian
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Daopeng Li
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Di Sun
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Xiaoqi Lv
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Chaoying Wang
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Changchuan Xie
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Luming Yao
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Caiming Wu
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Jin Hu
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Naian Xiao
- Department of Neurology, The First Affiliated Hospital, Xiamen University, Fujian, China
| | - Wei Mo
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
| | - Zhanxiang Wang
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
| | - Liang Zhang
- Department of Neuroscience, Institute of Neurosurgery, and Department of Neurosurgery, The First Affiliated Hospital, State Key Laboratory of Cellular Stress Biology, School of Medicine
- Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital
- School of Life Sciences, Innovation Center for Cell Signaling Network, and
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21
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Tokumoto Y, Araki Y, Narizuka Y, Mizuno Y, Ohshima S, Mimura T. Induction of memory-like CD8+ T cells and CD4+ T cells from human naive T cells in culture. Clin Exp Immunol 2022; 207:95-103. [PMID: 35020828 PMCID: PMC8802181 DOI: 10.1093/cei/uxab012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 11/14/2022] Open
Abstract
Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here, we describe a method to produce human memory-like T cells from naive human T cells in culture. Using commercially available human T-cell differentiation kits, both purified naive CD8+ T cells and purified naive CD4+ T cells were activated via T-cell receptor signaling and appropriate cytokines for several days in culture. All the T-cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T-cell activators were added back. We could also induce memory-like T cells from naive human T cells without hypoxia, if we froze the activated T cells or prepared the naive T cells from chilled filter buffy coats.
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Affiliation(s)
| | - Yasuto Araki
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yusuke Narizuka
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Yosuke Mizuno
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Susumu Ohshima
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Toshihide Mimura
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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22
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An J, Zhang Y, Fudge AD, Lu H, Richardson WD, Li H. G protein-coupled receptor GPR37-like 1 regulates adult oligodendrocyte generation. Dev Neurobiol 2021; 81:975-984. [PMID: 34601807 DOI: 10.1002/dneu.22854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/12/2021] [Accepted: 09/29/2021] [Indexed: 02/01/2023]
Abstract
Oligodendrocytes (OLs) continue to be generated from OL precursors (OPs) in the adult mammalian brain. Adult-born OLs are believed to contribute to neural plasticity, learning and memory through a process of "adaptive myelination," but how adult OL generation and adaptive myelination are regulated remains unclear. Here, we report that the glia-specific G protein-coupled receptor 37-like 1 (GPR37L1) is expressed in subsets of OPs and newly formed immature OLs in adult mouse brain. We found that OP proliferation and differentiation are inhibited in the corpus callosum of adult Gpr37l1 knockout mice, leading to a reduction in the number of adult-born OLs. Our data raise the possibility that GPR37L1 is mechanistically involved in adult OL generation and adaptive myelination, and suggest that GPR37L1 might be a useful functional marker of OPs that are committed to OL differentiation.
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Affiliation(s)
- Jing An
- Faculty of Medical Sciences, Division of Medicine, Wolfson Institute for Biomedical Research, University College London, London, UK.,School of Basic Medical Sciences, Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yumeng Zhang
- Faculty of Medical Sciences, Division of Medicine, Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Alexander D Fudge
- Faculty of Medical Sciences, Division of Medicine, Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Haixia Lu
- School of Basic Medical Sciences, Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - William D Richardson
- Faculty of Medical Sciences, Division of Medicine, Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Huiliang Li
- Faculty of Medical Sciences, Division of Medicine, Wolfson Institute for Biomedical Research, University College London, London, UK
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23
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Lloret A, Esteve D, Lloret MA, Monllor P, López B, León JL, Cervera-Ferri A. Is Oxidative Stress the Link Between Cerebral Small Vessel Disease, Sleep Disruption, and Oligodendrocyte Dysfunction in the Onset of Alzheimer's Disease? Front Physiol 2021; 12:708061. [PMID: 34512381 PMCID: PMC8424010 DOI: 10.3389/fphys.2021.708061] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/28/2021] [Indexed: 01/07/2023] Open
Abstract
Oxidative stress is an early occurrence in the development of Alzheimer’s disease (AD) and one of its proposed etiologic hypotheses. There is sufficient experimental evidence supporting the theory that impaired antioxidant enzymatic activity and increased formation of reactive oxygen species (ROS) take place in this disease. However, the antioxidant treatments fail to stop its advancement. Its multifactorial condition and the diverse toxicological cascades that can be initiated by ROS could possibly explain this failure. Recently, it has been suggested that cerebral small vessel disease (CSVD) contributes to the onset of AD. Oxidative stress is a central hallmark of CSVD and is depicted as an early causative factor. Moreover, data from various epidemiological and clinicopathological studies have indicated a relationship between CSVD and AD where endothelial cells are a source of oxidative stress. These cells are also closely related to oligodendrocytes, which are, in particular, sensitive to oxidation and lead to myelination being compromised. The sleep/wake cycle is another important control in the proliferation, migration, and differentiation of oligodendrocytes, and sleep loss reduces myelin thickness. Moreover, sleep plays a crucial role in resistance against CSVD, and poor sleep quality increases the silent markers of this vascular disease. Sleep disruption is another early occurrence in AD and is related to an increase in oxidative stress. In this study, the relationship between CSVD, oligodendrocyte dysfunction, and sleep disorders is discussed while focusing on oxidative stress as a common occurrence and its possible role in the onset of AD.
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Affiliation(s)
- Ana Lloret
- INCLIVA, CIBERFES, Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Daniel Esteve
- INCLIVA, CIBERFES, Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Maria Angeles Lloret
- Department of Clinical Neurophysiology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Paloma Monllor
- INCLIVA, CIBERFES, Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Begoña López
- Department of Neurology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - José Luis León
- Departament of Neuroradiology, Ascires Biomedical Group, Hospital Clinico Universitario, Valencia, Spain
| | - Ana Cervera-Ferri
- Department of Anatomy and Human Embryology, University of Valencia, Valencia, Spain
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24
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Kohnke S, Buller S, Nuzzaci D, Ridley K, Lam B, Pivonkova H, Bentsen MA, Alonge KM, Zhao C, Tadross J, Holmqvist S, Shimizu T, Hathaway H, Li H, Macklin W, Schwartz MW, Richardson WD, Yeo GSH, Franklin RJM, Karadottir RT, Rowitch DH, Blouet C. Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence. Cell Rep 2021; 36:109362. [PMID: 34260928 PMCID: PMC8293628 DOI: 10.1016/j.celrep.2021.109362] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/26/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
The mediobasal hypothalamus (MBH; arcuate nucleus of the hypothalamus [ARH] and median eminence [ME]) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here, we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNNs), emerging regulators of ARH metabolic functions, are rapidly remodeled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors. In genetically obese ob/ob mice, nutritional regulations of ME oligodendrocyte differentiation and PNN remodeling are blunted, and enzymatic digestion of local PNN increases food intake and weight gain. We conclude that MBH PNNs are required for the maintenance of energy balance in lean mice and are remodeled in the adult ME by the nutritional control of oligodendrocyte differentiation.
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Affiliation(s)
- Sara Kohnke
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Sophie Buller
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Danae Nuzzaci
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Katherine Ridley
- Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Brian Lam
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Helena Pivonkova
- Wellcome-MRC Cambridge Stem Cell Institute, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Marie A Bentsen
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Kimberly M Alonge
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Chao Zhao
- Wellcome-MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - John Tadross
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Staffan Holmqvist
- Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Takahiro Shimizu
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Hannah Hathaway
- Department of Cell & Developmental Biology and Program in Neuroscience, University of Colorado School of Medicine, Aurora, CO, USA
| | - Huiliang Li
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Wendy Macklin
- Department of Cell & Developmental Biology and Program in Neuroscience, University of Colorado School of Medicine, Aurora, CO, USA
| | - Michael W Schwartz
- University of Washington Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA
| | - William D Richardson
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Giles S H Yeo
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Robin J M Franklin
- Wellcome-MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Ragnhildur T Karadottir
- Wellcome-MRC Cambridge Stem Cell Institute, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - David H Rowitch
- Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Clemence Blouet
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
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25
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Ojeda-Pérez B, Campos-Sandoval JA, García-Bonilla M, Cárdenas-García C, Páez-González P, Jiménez AJ. Identification of key molecular biomarkers involved in reactive and neurodegenerative processes present in inherited congenital hydrocephalus. Fluids Barriers CNS 2021; 18:30. [PMID: 34215285 PMCID: PMC8254311 DOI: 10.1186/s12987-021-00263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/19/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Periventricular extracellular oedema, myelin damage, inflammation, and glial reactions are common neuropathological events that occur in the brain in congenital hydrocephalus. The periventricular white matter is the most affected region. The present study aimed to identify altered molecular and cellular biomarkers in the neocortex that can function as potential therapeutic targets to both treat and evaluate recovery from these neurodegenerative conditions. The hyh mouse model of hereditary hydrocephalus was used for this purpose. METHODS The hyh mouse model of hereditary hydrocephalus (hydrocephalus with hop gait) and control littermates without hydrocephalus were used in the present work. In tissue sections, the ionic content was investigated using energy dispersive X-ray spectroscopy scanning electron microscopy (EDS-SEM). For the lipid analysis, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed in frozen sections. The expression of proteins in the cerebral white matter was analysed by mass spectrometry. The oligodendrocyte progenitor cells (OPCs) were studied with immunofluorescence in cerebral sections and whole-mount preparations of the ventricle walls. RESULTS High sodium and chloride concentrations were found indicating oedema conditions in both the periventricular white matter and extending towards the grey matter. Lipid analysis revealed lower levels of two phosphatidylinositol molecular species in the grey matter, indicating that neural functions were altered in the hydrocephalic mice. In addition, the expression of proteins in the cerebral white matter revealed evident deregulation of the processes of oligodendrocyte differentiation and myelination. Because of the changes in oligodendrocyte differentiation in the white matter, OPCs were also studied. In hydrocephalic mice, OPCs were found to be reactive, overexpressing the NG2 antigen but not giving rise to an increase in mature oligodendrocytes. The higher levels of the NG2 antigen, diacylglycerophosphoserine and possibly transthyretin in the cerebrum of hydrocephalic hyh mice could indicate cell reactions that may have been triggered by inflammation, neurocytotoxic conditions, and ischaemia. CONCLUSION Our results identify possible biomarkers of hydrocephalus in the cerebral grey and white matter. In the white matter, OPCs could be reacting to acquire a neuroprotective role or as a delay in the oligodendrocyte maturation.
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Affiliation(s)
- Betsaida Ojeda-Pérez
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain
| | - José A Campos-Sandoval
- Servicios Centrales de Apoyo a la Investigación (SCAI), Universidad de Malaga, Malaga, Spain
| | - María García-Bonilla
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain
| | | | - Patricia Páez-González
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain.
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain.
| | - Antonio J Jiménez
- Department of Cell Biology, Genetics, and Physiology, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Malaga, Spain.
- Instituto de Investigación Biomédica de Málaga (IBIMA), Malaga, Spain.
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26
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Shin H, Kawai HD. Visual deprivation induces transient upregulation of oligodendrocyte progenitor cells in the subcortical white matter of mouse visual cortex. IBRO Neurosci Rep 2021; 11:29-41. [PMID: 34286312 PMCID: PMC8273201 DOI: 10.1016/j.ibneur.2021.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Sensory experience influences proliferation and differentiation of oligodendrocyte progenitor cells (OPCs). Enhanced sensorimotor experience promoted the lineage progression of OPCs and myelination in the gray matter and white matter (WM) of sensorimotor cortex. In the visual cortex, reduced experience reportedly delayed the maturation of myelination in the gray matter, but whether and how such experience alters the subcortical WM is unclear. Here we investigated if binocular enucleation from the onset of eye opening (i.e., P15) affects the cell state of OPCs in mouse primary visual cortex (V1). Proliferative cells in the WM declined nearly half over 3 days from postnatal day (P) 25. A 3-day BrdU-labeling showed gradual decline in proliferation rates from P19 to P28. Binocular enucleation resulted in an increase in the cycling state of the OPCs that were proliferated from P22 to P25 but not before or after this period. This increase in proliferative OPCs was not associated with lineage progression toward differentiated oligodendrocytes. Proliferative OPCs arose mostly due to symmetric cell division but also asymmetric formation of proliferative and quiescent OPCs. By P30, almost all the proliferated cells exited the cell cycle. Maturing oligodendrocytes among the proliferated cells increased at this age, but most of them disappeared over 25 days. The cell density of the maturing oligodendrocytes was unaffected by binocular enucleation, however. These data suggest that binocular enucleation transiently elevates proliferative OPCs in the subcortical WM of V1 during a specific period of the fourth postnatal week without subsequently affecting the number of maturing oligodendrocytes several days later.
Binocular enucleation increased proliferative OPCs during P22-25 in the V1 WM. Proliferative OPCs decrease in half from P25 over 3 days. P22-25 proliferated cells nearly all exited the cell cycle by P30. Some P22-25 proliferated OPCs matured over 5 days but disappeared over 25 days. Visual loss did not influence oligodendrocyte maturation or its disappearance.
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Affiliation(s)
- Hyeryun Shin
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
| | - Hideki Derek Kawai
- Department of Biosciences, Graduate School of Science and Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
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27
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Mitchell-Dick A, Asokan A. AAV-CNS matters turn from gray to white. Mol Ther 2021; 29:1659-1660. [PMID: 33891861 DOI: 10.1016/j.ymthe.2021.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
| | - Aravind Asokan
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
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28
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Dual Roles of Microglia in the Basal Ganglia in Parkinson's Disease. Int J Mol Sci 2021; 22:ijms22083907. [PMID: 33918947 PMCID: PMC8070536 DOI: 10.3390/ijms22083907] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/30/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
With the increasing age of the population, the incidence of Parkinson’s disease (PD) has increased exponentially. The development of novel therapeutic interventions requires an understanding of the involvement of senescent brain cells in the pathogenesis of PD. In this review, we highlight the roles played by microglia in the basal ganglia in the pathophysiological processes of PD. In PD, dopaminergic (DAergic) neuronal degeneration in the substantia nigra pars compacta (SNc) activates the microglia, which then promote DAergic neuronal degeneration by releasing potentially neurotoxic factors, including nitric oxide, cytokines, and reactive oxygen species. On the other hand, microglia are also activated in the basal ganglia outputs (the substantia nigra pars reticulata and the globus pallidus) in response to excess glutamate released from hyperactive subthalamic nuclei-derived synapses. The activated microglia then eliminate the hyperactive glutamatergic synapses. Synapse elimination may be the mechanism underlying the compensation that masks the appearance of PD symptoms despite substantial DAergic neuronal loss. Microglial senescence may correlate with their enhanced neurotoxicity in the SNc and the reduced compensatory actions in the basal ganglia outputs. The dual roles of microglia in different basal ganglia regions make it difficult to develop interventions targeting microglia for PD treatment.
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29
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Identifying a Population of Glial Progenitors That Have Been Mistaken for Neurons in Embryonic Mouse Cortical Culture. eNeuro 2021; 8:ENEURO.0388-20.2020. [PMID: 33483322 PMCID: PMC7986526 DOI: 10.1523/eneuro.0388-20.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/16/2020] [Accepted: 12/28/2020] [Indexed: 12/17/2022] Open
Abstract
Experiments in primary culture have helped advance our understanding of the curious phenomenon of cell cycle-related neuronal death. In a differentiated postmitotic cell such as a neuron, aberrant cell cycle reentry is strongly associated with apoptosis. Indeed, in many pathologic conditions, neuronal populations at risk for death are marked by cells engaged in a cell cycle like process. The evidence for this conclusion is typically based on finding MAP2+ cells that are also positive for cell cycle-related proteins (e.g., cyclin D) or have incorporated thymidine analogs such as bromodeoxyuridine (BrdU) or 5-ethynyl-2’-deoxyuridine (EdU) into their nuclei. We now report that we and others may have partly been led astray in pursuing this line of work. Morphometric analysis of mouse embryonic cortical cultures reveals that the size of the “cycling” MAP2+ cells is significantly smaller than those of normal neurons, and their expression of MAP2 is significantly lower. This led us to ask whether, rather than representing fully developed neurons, they more closely resembled precursor-like cells. In support of this idea, we find that these small MAP2+ cells are immunopositive for nestin, a neuronal precursor marker, Olig2, an oligodendrocyte lineage marker, and neural/glial antigen 2 (NG2), an oligodendrocyte precursor marker. Tracking their behavior in culture, we find that they predominantly give rise to GFAP+ astrocytes instead of neurons or oligodendrocytes. These findings argue for a critical reexamination of previous reports of stimuli that lead to neuronal cell cycle-related death in primary cultures.
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30
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Hassanzadeh S, Jalessi M, Jameie SB, Khanmohammadi M, Bagher Z, Namjoo Z, Davachi SM. More attention on glial cells to have better recovery after spinal cord injury. Biochem Biophys Rep 2021; 25:100905. [PMID: 33553683 PMCID: PMC7844125 DOI: 10.1016/j.bbrep.2020.100905] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 01/01/2023] Open
Abstract
Functional improvement after spinal cord injury remains an unsolved difficulty. Glial scars, a major component of SCI lesions, are very effective in improving the rate of this recovery. Such scars are a result of complex interaction mechanisms involving three major cells, namely, astrocytes, oligodendrocytes, and microglia. In recent years, scientists have identified two subtypes of reactive astrocytes, namely, A1 astrocytes that induce the rapid death of neurons and oligodendrocytes, and A2 astrocytes that promote neuronal survival. Moreover, recent studies have suggested that the macrophage polarization state is more of a continuum between M1 and M2 macrophages. M1 macrophages that encourage the inflammation process kill their surrounding cells and inhibit cellular proliferation. In contrast, M2 macrophages promote cell proliferation, tissue growth, and regeneration. Furthermore, the ability of oligodendrocyte precursor cells to differentiate into adult oligodendrocytes or even neurons has been reviewed. Here, we first scrutinize recent findings on glial cell subtypes and their beneficial or detrimental effects after spinal cord injury. Second, we discuss how we may be able to help the functional recovery process after injury.
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Affiliation(s)
- Sajad Hassanzadeh
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Jalessi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Behnamedin Jameie
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Basic Sciences, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Zohre Bagher
- ENT and Head & Neck Research Center and Department, The Five Senses Health Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Namjoo
- Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Seyed Mohammad Davachi
- Department of Food Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA
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31
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Su X, Vasilkovska T, Fröhlich N, Garaschuk O. Characterization of cell type-specific S100B expression in the mouse olfactory bulb. Cell Calcium 2021; 94:102334. [PMID: 33460952 DOI: 10.1016/j.ceca.2020.102334] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 12/17/2022]
Abstract
S100B is an EF-hand type Ca2+-binding protein of the S100 family, known to support neurogenesis and to promote the interactions between brain's nervous and immune systems. Here, we characterized the expression of S100B in the mouse olfactory bulb, a neurogenic niche comprising mature and adult-born neurons, astrocytes, oligodendrocytes and microglia. Besides astrocytes, for which S100B is a classical marker, S100B was also expressed in NG2 cells and, surprisingly, in APC-positive myelinating oligodendrocytes but not in mature/adult-born neurons or microglia. Various layers of the bulb differed substantially in the composition of S100B-positive cells, with the highest fraction of the APC-positive oligodendrocytes found in the granule cell layer. Across all layers, ∼50 % of NG2 cells were S100B-negative. Finally, our data revealed a strong correlation between the fraction of myelinating oligodendrocytes among the S100B-positive cells and the oligodendrocyte density in different brain areas, underscoring the importance of S100B for the establishment and maintenance of myelin sheaths.
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Affiliation(s)
- Xin Su
- Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tamara Vasilkovska
- Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Nicole Fröhlich
- Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Olga Garaschuk
- Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany.
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32
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Akay LA, Effenberger AH, Tsai LH. Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function. Genes Dev 2021; 35:180-198. [PMID: 33526585 PMCID: PMC7849363 DOI: 10.1101/gad.344218.120] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) are not merely a transitory progenitor cell type, but rather a distinct and heterogeneous population of glia with various functions in the developing and adult central nervous system. In this review, we discuss the fate and function of OPCs in the brain beyond their contribution to myelination. OPCs are electrically sensitive, form synapses with neurons, support blood-brain barrier integrity, and mediate neuroinflammation. We explore how sex and age may influence OPC activity, and we review how OPC dysfunction may play a primary role in numerous neurological and neuropsychiatric diseases. Finally, we highlight areas of future research.
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Affiliation(s)
- Leyla Anne Akay
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Audrey H Effenberger
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Li-Huei Tsai
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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de Curtis M, Garbelli R, Uva L. A hypothesis for the role of axon demyelination in seizure generation. Epilepsia 2021; 62:583-595. [PMID: 33493363 DOI: 10.1111/epi.16824] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 01/06/2023]
Abstract
Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.
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Affiliation(s)
- Marco de Curtis
- Epilepsy Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy
| | - Rita Garbelli
- Epilepsy Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy
| | - Laura Uva
- Epilepsy Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy
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Zhou B, Zhu Z, Ransom BR, Tong X. Oligodendrocyte lineage cells and depression. Mol Psychiatry 2021; 26:103-117. [PMID: 33144710 PMCID: PMC7815509 DOI: 10.1038/s41380-020-00930-0] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/01/2020] [Accepted: 10/22/2020] [Indexed: 12/25/2022]
Abstract
Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic-pituitary-adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.
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Affiliation(s)
- Butian Zhou
- Center for Brain Science, Shanghai Children's Medical Center; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhongqun Zhu
- Department of Cardiothoracic Surgery, Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bruce R Ransom
- Neuroscience Department, City University of Hong Kong, Hong Kong, China.
| | - Xiaoping Tong
- Center for Brain Science, Shanghai Children's Medical Center; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Abstract
In the mammalian central nervous system, nerve-glia antigen 2 (NG2) glia are considered the fourth glial population in addition to astrocytes, oligodendrocytes and microglia. The fate of NG2 glia in vivo has been carefully studied in several transgenic mouse models using the Cre/loxP strategy. There is a clear agreement that NG2 glia mainly serve as progenitors for oligodendrocytes and a subpopulation of astrocytes mainly in the ventral forebrain, whereas the existence of a neurogenic potential of NG2 glia is lack of adequate evidence. This mini review summarizes the findings from recent studies regarding the fate of NG2 glia during development. We will highlight the age-and-region-dependent heterogeneity of the NG2 glia differentiation potential. We will also discuss putative reasons for inconsistent findings in various transgenic mouse lines of previous studies.
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Affiliation(s)
- Qilin Guo
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
| | - Anja Scheller
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
| | - Wenhui Huang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Homburg, Germany
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Haase S, Nuñez FM, Gauss JC, Thompson S, Brumley E, Lowenstein P, Castro MG. Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities. Int J Mol Sci 2020; 21:ijms21249654. [PMID: 33348922 PMCID: PMC7766684 DOI: 10.3390/ijms21249654] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022] Open
Abstract
In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.
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Affiliation(s)
- Santiago Haase
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Fernando M. Nuñez
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jessica C. Gauss
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sarah Thompson
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Emily Brumley
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Pedro Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Maria G. Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (S.H.); (F.M.N.); (J.C.G.); (S.T.); (E.B.); (P.L.)
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Correspondence:
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Unraveling the adult cell progeny of early postnatal progenitor cells. Sci Rep 2020; 10:19058. [PMID: 33149241 PMCID: PMC7643156 DOI: 10.1038/s41598-020-75973-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/18/2020] [Indexed: 02/07/2023] Open
Abstract
NG2-glia, also referred to as oligodendrocyte precursor cells or polydendrocytes, represent a large pool of proliferative neural cells in the adult brain that lie outside of the two major adult neurogenic niches. Although their roles are not fully understood, we previously reported significant clonal expansion of adult NG2-cells from embryonic pallial progenitors using the StarTrack lineage-tracing tool. To define the contribution of early postnatal progenitors to the specific NG2-glia lineage, we used NG2-StarTrack. A temporal clonal analysis of single postnatal progenitor cells revealed the production of different glial cell types in distinct areas of the dorsal cortex but not neurons. Moreover, the dispersion and size of the different NG2 derived clonal cell clusters increased with age. Indeed, clonally-related NG2-glia were located throughout the corpus callosum and the deeper layers of the cortex. In summary, our data reveal that postnatally derived NG2-glia are proliferative cells that give rise to NG2-cells and astrocytes but not neurons. These progenitors undergo clonal cell expansion and dispersion throughout the adult dorsal cortex in a manner that was related to aging and cell identity, adding new information about the ontogeny of these cells. Thus, identification of clonally-related cells from specific progenitors is important to reveal the NG2-glia heterogeneity.
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Snaidero N, Schifferer M, Mezydlo A, Zalc B, Kerschensteiner M, Misgeld T. Myelin replacement triggered by single-cell demyelination in mouse cortex. Nat Commun 2020; 11:4901. [PMID: 32994410 PMCID: PMC7525521 DOI: 10.1038/s41467-020-18632-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel, patchy isolated internodes emerge on previously unmyelinated axons. Therefore, in mammalian cortex, internodes along partially myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, myelin sheaths forming continuous patterns show remarkable homeostatic resilience and remyelinate with single axon precision.
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Affiliation(s)
- Nicolas Snaidero
- Institute of Neuronal Cell Biology, Technische Universität München, 80802, Munich, Germany.
- German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany.
- Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, 81377, Munich, Germany.
- Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, 82152, Martinsried, Germany.
| | - Martina Schifferer
- German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Aleksandra Mezydlo
- Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, 81377, Munich, Germany
- Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, 82152, Martinsried, Germany
| | - Bernard Zalc
- Inserm, CNRS, Institut du Cerveau, Pitié-Salpêtrière Hospital, Sorbonne Université, 75013, Paris, France
| | - Martin Kerschensteiner
- Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians Universität München, 81377, Munich, Germany
- Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians Universität München, 82152, Martinsried, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Thomas Misgeld
- Institute of Neuronal Cell Biology, Technische Universität München, 80802, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Abstract
The central nervous system is simply divided into two distinct anatomical regions based on the color of tissues, i.e. the gray and white matter. The gray matter is composed of neuronal cell bodies, glial cells, dendrites, immune cells, and the vascular system, while the white matter is composed of concentrated myelinated axonal fibers extending from neuronal soma and glial cells, such as oligodendrocyte precursor cells (OPCs), oligodendrocytes, astrocytes, and microglia. As neuronal cell bodies are located in the gray matter, great attention has been focused mainly on the gray matter regarding the understanding of the functions of the brain throughout the neurophysiological areas, leading to a scenario in which the function of the white matter is relatively underestimated or has not received much attention. However, increasing evidence shows that the white matter plays highly significant and pivotal functions in the brain based on the fact that its abnormalities are associated with numerous neurological diseases. In this review, we will broadly discuss the pathways and functions of myelination, which is one of the main processes that modulate the functions of the white matter, as well as the manner in which its abnormalities are related to neurological disorders.
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40
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Abstract
While neurons and circuits are almost unequivocally considered to be the computational units and actuators of behavior, a complete understanding of the nervous system must incorporate glial cells. Far beyond a copious but passive substrate, glial influence is inextricable from neuronal physiology, whether during developmental guidance and synaptic shaping or through the trophic support, neurotransmitter and ion homeostasis, cytokine signaling and immune function, and debris engulfment contributions that this class provides throughout an organism's life. With such essential functions, among a growing literature of nuanced roles, it follows that glia are consequential to behavior in adult animals, with novel genetic tools allowing for the investigation of these phenomena in living organisms. We discuss here the relevance of glia for maintaining circadian rhythms and also for serving functions of sleep.
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Affiliation(s)
- Gregory Artiushin
- Chronobiology and Sleep Institute, Perelman School of Medicine, and Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
| | - Amita Sehgal
- Chronobiology and Sleep Institute, Perelman School of Medicine, and Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
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41
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Sánchez-González R, Bribián A, López-Mascaraque L. Cell Fate Potential of NG2 Progenitors. Sci Rep 2020; 10:9876. [PMID: 32555386 PMCID: PMC7303219 DOI: 10.1038/s41598-020-66753-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 05/26/2020] [Indexed: 11/11/2022] Open
Abstract
Determining the origin of different glial subtypes is crucial to understand glial heterogeneity, and to enhance our knowledge of glial and progenitor cell behavior in embryos and adults. NG2-glia are homogenously distributed in a grid-like manner in both, gray and white matter of the adult brain. While some NG2-glia in the CNS are responsible for the generation of mature oligodendrocytes (OPCs), most of them do not differentiate and they can proliferate outside of adult neurogenic niches. Thus, NG2-glia constitute a heterogeneous population containing different subpopulations with distinct functions. We hypothesized that their diversity emerges from specific progenitors during development, as occurs with other glial cell subtypes. To specifically target NG2-pallial progenitors and to define the NG2-glia lineage, as well as the NG2-progenitor potential, we designed two new StarTrack strategies using the NG2 promoter. These approaches label NG2 expressing progenitor cells, permitting the cell fates of these NG2 progenitors to be tracked in vivo. StarTrack labelled cells producing different neural phenotypes in different regions depending on the age targeted, and the strategy selected. This specific genetic targeting of neural progenitors in vivo has provided new data on the heterogeneous pool of NG2 progenitors at both embryonic and postnatal ages.
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Functional Heterogeneity of Mouse and Human Brain OPCs: Relevance for Preclinical Studies in Multiple Sclerosis. J Clin Med 2020; 9:jcm9061681. [PMID: 32498223 PMCID: PMC7355819 DOI: 10.3390/jcm9061681] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 05/19/2020] [Indexed: 02/08/2023] Open
Abstract
Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs for the first time with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.
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Alt EU, Winnier G, Haenel A, Rothoerl R, Solakoglu O, Alt C, Schmitz C. Towards a Comprehensive Understanding of UA-ADRCs (Uncultured, Autologous, Fresh, Unmodified, Adipose Derived Regenerative Cells, Isolated at Point of Care) in Regenerative Medicine. Cells 2020; 9:E1097. [PMID: 32365488 PMCID: PMC7290808 DOI: 10.3390/cells9051097] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/18/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither 'fat stem cells' nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.
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Affiliation(s)
- Eckhard U. Alt
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA
- Sanford Health, University of South Dakota, Sioux Falls, SD 57104, USA
- University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Isar Klinikum Munich, 80331 Munich, Germany
- InGeneron, Inc., Houston, TX 77054, USA
| | | | - Alexander Haenel
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA
- Department of Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, 23562 Lübeck, Germany
| | | | - Oender Solakoglu
- Dental Department of the University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Periodontology and Implant Dentistry, 22453 Hamburg, Germany
| | | | - Christoph Schmitz
- Institute of Anatomy, Faculty of Medicine, LMU Munich, 80331 Munich, Germany
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Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation. Nat Neurosci 2020; 23:363-374. [PMID: 32066987 PMCID: PMC7292734 DOI: 10.1038/s41593-019-0581-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/20/2019] [Indexed: 01/06/2023]
Abstract
Recent reports have revealed oligodendrocyte precursor cell (OPC)
heterogeneity. It remains unclear if such heterogeneity reflects different
subtypes of cells with distinct functions, or rather transiently acquired states
of cells with the same function. By integrating lineage formation of individual
OPC clones, single-cell transcriptomics, calcium imaging and neural activity
manipulation, we show that OPCs in the zebrafish spinal cord can be divided into
two functionally distinct groups. One subgroup forms elaborate networks of
processes and exhibits a high degree of calcium signalling, but infrequently
differentiates, despite contact with permissive axons. Instead, these OPCs
divide in an activity and calcium dependent manner to produce another subgroup
with higher process motility and less calcium signaling, which readily
differentiates. Our data show that OPC subgroups are functionally diverse in
responding to neurons and reveal that activity regulates proliferation of a
subset of OPCs that is distinct from the cells that generate differentiated
oligodendrocytes.
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45
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Abstract
Survival motor neuron (SMN) deficiency indicates that various cellular processes are impaired in spinal muscular atrophy (SMA). Previous reports have shown that SMN deficiency causes motor neuron degeneration, whereas the numbers of astrocytes and microglia are significantly increased or activated in SMA model systems. Only a few groups have studied the role of oligodendrocyte (OL) lineages such as OL precursor cell and nerve/glial antigen 2 (NG2)-glia in SMA pathology. Our aim in this study was to investigate whether OL lineages are impaired in SMA model systems. We investigated the expression of myelin basic protein (MBP) and NG2, which are OL lineage markers, using SMNΔ7 mice (mSmn, SMN2, SMNΔ7) and cell cultures derived from induced pluripotent stem cells generated from SMA patients. We showed for the first time that the OL lineages, including NG2-positive OL precursor cells and MBP-positive myelinating OLs were impaired in SMNΔ7 mice and induced pluripotent stem cells derived from SMA patients. Notch was involved in the decline of NG2 expression in the spinal cord of SMNΔ7 mice. In addition, pharmacological Notch inhibition promoted MBP-positive OL differentiation in SMNΔ7 mice. These findings indicate that OL differentiation was impaired in SMA, which might be involved in the Notch dysregulation.
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Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model. Cells 2019; 8:cells8121550. [PMID: 31801252 PMCID: PMC6953036 DOI: 10.3390/cells8121550] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023] Open
Abstract
The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor, mediating endocytosis and activating intracellular signaling cascades. LRP1 is highly expressed in the central nervous system (CNS), especially in oligodendrocyte precursor cells (OPCs). Previous studies have suggested LRP1 as a regulator in early oligodendrocyte development, repair of chemically induced white matter lesions, and cholesterol homeostasis. To circumvent embryonic lethality observed in the case of global LRP1 deletion, we generated a new inducible conditional knockout (KO) mouse model, which enabled an NG2-restricted LRP1 deficiency (NG2-CreERT2ct2/wtxR26eGFPflox/floxxLRP1flox/flox). When characterizing our triple transgenic mouse model, we noticed a substantial and progressive loss of recombined LRP1-deficient cells in the oligodendrocyte lineage. On the other hand, we found comparable distributions and fractions of oligodendroglia within the Corpus callosum of the KO and control animals, indicating a compensation of these deficits. An initial study on experimental autoimmune encephalomyelitis (EAE) was performed in triple transgenic and control mice and the cell biology of oligodendrocytes obtained from the animals was studied in an in vitro myelination assay. Differences could be observed in these assays, which, however, did not achieve statistical significance, presumably because the majority of recombined LRP1-deficient cells has been replaced by non-recombined cells. Thus, the analysis of the role of LRP1 in EAE will require the induction of acute recombination in the context of the disease process. As LRP1 is necessary for the survival of OPCs in vivo, we assume that it will play an important role in myelin repair.
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de Vivo L, Bellesi M. The role of sleep and wakefulness in myelin plasticity. Glia 2019; 67:2142-2152. [PMID: 31237382 PMCID: PMC6771952 DOI: 10.1002/glia.23667] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/17/2022]
Abstract
Myelin plasticity is gaining increasing recognition as an essential partner to synaptic plasticity, which mediates experience-dependent brain structure and function. However, how neural activity induces adaptive myelination and which mechanisms are involved remain open questions. More than two decades of transcriptomic studies in rodents have revealed that hundreds of brain transcripts change their expression in relation to the sleep-wake cycle. These studies consistently report upregulation of myelin-related genes during sleep, suggesting that sleep represents a window of opportunity during which myelination occurs. In this review, we summarize recent molecular and morphological studies detailing the dependence of myelin dynamics after sleep, wake, and chronic sleep loss, a condition that can affect myelin substantially. We present novel data about the effects of sleep loss on the node of Ranvier length and provide a hypothetical mechanism through which myelin changes in response to sleep loss. Finally, we discuss the current findings in humans, which appear to confirm the important role of sleep in promoting white matter integrity.
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Affiliation(s)
- Luisa de Vivo
- School of Physiology, Pharmacology and NeuroscienceUniversity of BristolBristolUK
| | - Michele Bellesi
- School of Physiology, Pharmacology and NeuroscienceUniversity of BristolBristolUK
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Boshans LL, Sherafat A, Nishiyama A. The effects of developmental and current niches on oligodendrocyte precursor dynamics and fate. Neurosci Lett 2019; 715:134593. [PMID: 31678373 DOI: 10.1016/j.neulet.2019.134593] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/29/2022]
Abstract
Oligodendrocyte precursor cells (OPCs), whose primary function is to generate myelinating oligodendrocytes, are distributed widely throughout the developing and mature central nervous system. They originate from several defined subdomains in the embryonic germinal zones at different developmental stages and in the adult. While many phenotypic differences have been observed among OPCs in different anatomical regions and among those arising from different germinal zones, we know relatively little about the molecular and cellular mechanisms by which the historical and current niches shape the behavior of oligodendrocyte lineage cells. This minireview will discuss how the behavior of oligodendrocyte lineage cells is influenced by the developmental niches from which subpopulations of OPCs emerge, by the current niches surrounding OPCs in different regions, and in pathological states that cause deviations from the normal density of oligodendrocyte lineage cells and myelin.
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Affiliation(s)
- Linda L Boshans
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, 06269, USA
| | - Amin Sherafat
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, 06269, USA
| | - Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, 06269, USA; Institute for Systems Genomics, University of Connecticut, USA; Institute for Brain and Cognitive Science, University of Connecticut, USA.
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Pitman KA, Ricci R, Gasperini R, Beasley S, Pavez M, Charlesworth J, Foa L, Young KM. The voltage-gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex. Glia 2019; 68:376-392. [PMID: 31605513 PMCID: PMC6916379 DOI: 10.1002/glia.23723] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 09/02/2019] [Accepted: 09/10/2019] [Indexed: 12/21/2022]
Abstract
Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes. OPCs express cell surface receptors and channels that allow them to detect and respond to neuronal activity, including voltage‐gated calcium channel (VGCC)s. The major L‐type VGCC expressed by developmental OPCs, CaV1.2, regulates their differentiation. However, it is unclear whether CaV1.2 similarly influences OPC behavior in the healthy adult central nervous system (CNS). To examine the role of CaV1.2 in adulthood, we conditionally deleted this channel from OPCs by administering tamoxifen to P60 Cacna1cfl/fl (control) and Pdgfrα‐CreER:: Cacna1cfl/fl (CaV1.2‐deleted) mice. Whole cell patch clamp analysis revealed that CaV1.2 deletion reduced L‐type voltage‐gated calcium entry into adult OPCs by ~60%, confirming that it remains the major L‐type VGCC expressed by OPCs in adulthood. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2‐deleted mice had an OPC density ~42% that of control mice. OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2‐deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, we conclude that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs but not for all OPCs in the mature CNS.
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Affiliation(s)
- Kimberley A Pitman
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Raphael Ricci
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Robert Gasperini
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.,School of Medicine, University of Tasmania, Hobart, Australia
| | - Shannon Beasley
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Macarena Pavez
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Jac Charlesworth
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Lisa Foa
- School of Medicine, University of Tasmania, Hobart, Australia
| | - Kaylene M Young
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
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Abstract
Leukodystrophies are genetically determined disorders affecting the white matter of the central nervous system. The combination of MRI pattern recognition and next-generation sequencing for the definition of novel disease entities has recently demonstrated that many leukodystrophies are due to the primary involvement and/or mutations in genes selectively expressed by cell types other than the oligodendrocytes, the myelin-forming cells in the brain. This has led to a new definition of leukodystrophies as genetic white matter disorders resulting from the involvement of any white matter structural component. As a result, the research has shifted its main focus from oligodendrocytes to other types of neuroglia. Astrocytes are the housekeeping cells of the nervous system, responsible for maintaining homeostasis and normal brain physiology and to orchestrate repair upon injury. Several lines of evidence show that astrocytic interactions with the other white matter cellular constituents play a primary pathophysiologic role in many leukodystrophies. These are thus now classified as astrocytopathies. This chapter addresses how the crosstalk between astrocytes, other glial cells, axons and non-neural cells are essential for the integrity and maintenance of the white matter in health. It also addresses the current knowledge of the cellular pathomechanisms of astrocytic leukodystrophies, and specifically Alexander disease, vanishing white matter, megalencephalic leukoencephalopathy with subcortical cysts and Aicardi-Goutière Syndrome.
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Affiliation(s)
- M S Jorge
- Department of Pathology, Free University Medical Centre, Amsterdam, The Netherlands
| | - Marianna Bugiani
- Department of Pathology, Free University Medical Centre, Amsterdam, The Netherlands.
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