The Experts below are selected from a list of 1383 Experts worldwide ranked by ideXlab platform
Arthur M Butt - One of the best experts on this subject based on the ideXlab platform.
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disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of alzheimer s disease
Neurobiology of Aging, 2020Co-Authors: Ilaria Vanzulli, Andrea Rivera, Maria Papanikolaou, Irene Chacon Delarocha, Francesca Pieropan, Diego Gomeznicola, Alexei Verkhratsky, Jose J Rodriguez, Arthur M ButtAbstract:Abstract There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-Glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-β (Aβ) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.
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physiology of oligodendroGlia
Advances in Experimental Medicine and Biology, 2019Co-Authors: Arthur M Butt, Maria Papanikolaou, Andrea RiveraAbstract:Oligodendrocytes are the myelinating cells of the CNS, producing the insulating myelin sheath that facilitates rapid electrical conduction of axonal action potentials. Oligodendrocytes arise from oligodendrocyte progenitor cells (OPCs) under the control of multiple factors, including neurotransmitters and other neuron-derived factors. A significant population of OPCs persists in the adult CNS, where they are often referred to as NG2-Glia, because they are identified by their expression of the NG2 chondroitin sulphate proteoglycan (CSPG4). In the adult brain, the primary function of NG2-Glia is the life-long generation of oligodendrocytes to replace myelin lost through natural 'wear and tear' and pathology, as well as to provide new oligodendrocytes to myelinate new connections formed in response to new life experiences. NG2-Glia contact synapses and respond to neurotransmitters and potassium released during neuronal transmission; to this end, NG2-Glia (OPCs) express multiple neurotransmitter receptors and ion channels, with prominent roles being identified for glutamatergic signalling and potassium channels in oligodendrocyte differentiation. Myelinating oligodendrocytes also express a wide range of neurotransmitter receptors and ion channels, together with transporters and gap junctions; together, these have critical functions in cellular ion and water homeostasis, as well as metabolism, which is essential for maintaining myelin and axon integrity. An overriding theme is that oligodendrocyte function and myelination is not only essential for rapid axonal conduction, but is essential for learning and the long-term integrity of axons and neurones. Hence, myelination underpins cognitive function and the massive computing power of the human brain and myelin loss has devastating effects on CNS function. This chapter focuses on normal oligodendrocyte physiology.
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METHODS Immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan
2016Co-Authors: Giampaolo Leoni, Andrea Rivera, Marcus Rattray, Daniel Fulton, Arthur M ButtAbstract:Expression of the transmembrane NG2 chondroitin sulphate proteoglycan (CSPG) defines a distinct population of NG2-Glia. NG2-Glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system (CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the Glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-Glia form unique neuron–Glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-Glia in any of these functions using conventional transgenic NG2 ‘knockout ’ mice. To overcome this, we aimed to determine whether NG2-Glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti-NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-Glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-Glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration. Key words: Glia; immunoablation; immunotoxin; NG2 proteoglycan; oligodendrocyte progenitor cells; oligodendrocyte precursor cells
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decreased regenerative capacity of oligodendrocyte progenitor cells NG2 Glia in the ageing brain a vicious cycle of synaptic dysfunction myelin loss and neuronal disruption
Current Alzheimer Research, 2016Co-Authors: Andrea Rivera, Ilaria Vanzuli, Jose Julio Rodriguez Arellano, Arthur M ButtAbstract:Oligodendrocytes are specialised Glial cells that myelinate CNS axons. Myelinated axons are bundled together into white matter tracts that interconnect grey matter areas of the brain and are essential for rapid, integrated neuronal communication and cognitive function. Life-long generation of oligodendrocytes is required for myelination of new neuronal connections and repair of myelin lost through natural 'wear and tear'. This is the function of a substantial population of adult oligodendrocyte progenitors (OPs). Notably, there is white matter shrinkage and decreased myelination in the ageing brain, which is accelerated in dementia. The underlying causes of myelin loss in dementia are unresolved, but it implies a decline in the regenerative capacity of OPs. A feature of OPs is that they form neuron-Glial synapses and respond to glutamate released by neurons via a range of glutamate receptors. Glutamate neurotransmission onto OPs is proposed to regulate their proliferation and differentiation into myelinating oligodendrocytes. Here, we discuss evidence that deregulation of glutamate neurotransmission in dementia and compromised generation of oligodendrocytes from OPs are key features of myelin loss and associated cognitive decline.
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immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan
Journal of Anatomy, 2014Co-Authors: Giampaolo Leoni, Andrea Rivera, Marcus Rattray, Daniel Fulton, Arthur M ButtAbstract:Expression of the transmembrane NG2 chondroitin sulphate proteoglycan (CSPG) defines a distinct population of NG2-Glia. NG2-Glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system (CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the Glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-Glia form unique neuron–Glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-Glia in any of these functions using conventional transgenic NG2 ‘knockout’ mice. To overcome this, we aimed to determine whether NG2-Glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti-NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-Glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-Glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration.
Leda Dimou - One of the best experts on this subject based on the ideXlab platform.
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Glial cells and their function in the adult brain a journey through the history of their ablation
Frontiers in Cellular Neuroscience, 2017Co-Authors: Sarah Jakel, Leda DimouAbstract:Glial cells, consisting of microGlia, astrocytes and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of Glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different Glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microGlia, astrocytes or oligodendrocyte lineage cells (i.e. NG2-Glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different Glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all Glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review we will give a detailed summary on different Glial ablation studies, focusing on the adult mouse central nervous system (CNS) and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future.
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NG2-Glia and their functions in the central nervous system
Glia, 2015Co-Authors: Leda Dimou, Vittorio GalloAbstract:In the central nervous system, NG2-Glia represent a neural cell population that is distinct from neurons, astrocytes, and oligodendrocytes. While in the past the main role ascribed to these cells was that of progenitors for oligodendrocytes, in the last years it has become more obvious that they have further functions in the brain. Here, we will discuss some of the most current and highly debated issues regarding NG2-Glia: Do these cells represent a heterogeneous population? Can they give rise to different progenies, and does this change under pathological conditions? How do they respond to injury or pathology? What is the role of neurotransmitter signaling between neurons and NG2-Glia? We will first give an overview on the developmental origin of NG2-Glia, and then discuss whether their distinct properties in different brain regions are the result of environmental influences, or due to intrinsic differences. We will then review and discuss their in vitro differentiation potential and in vivo lineage under physiological and pathological conditions, together with their electrophysiological properties in distinct brain regions and at different developmental stages. Finally, we will focus on their potential to be used as therapeutic targets in demyelinating and neurodegenerative diseases. Therefore, this review article will highlight the importance of NG2-Glia not only in the healthy, but also in the diseased brain. Glia 2015;63:1429–1451
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sox2 mediated conversion of NG2 Glia into induced neurons in the injured adult cerebral cortex
Stem cell reports, 2014Co-Authors: Christophe Heinrich, Leda Dimou, Matteo Bergami, Sergio Gascon, Alexandra Lepier, Francesca Vigano, Bernd Sutor, Benedikt Berninger, Magdalena GötzAbstract:The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 Glia into induced doublecortin (DCX)+ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroGlial and astroGlial cells into DCX+ cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 Glia represent a potential target for reprogramming strategies toward cortical repair.
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Glial cells as progenitors and stem cells new roles in the healthy and diseased brain
Physiological Reviews, 2014Co-Authors: Leda Dimou, Magdalena GötzAbstract:The diverse functions of Glial cells prompt the question to which extent specific subtypes may be devoted to a specific function. We discuss this by reviewing one of the most recently discovered roles of Glial cells, their function as neural stem cells (NSCs) and progenitor cells. First we give an overview of Glial stem and progenitor cells during development; these are the radial Glial cells that act as NSCs and other Glial progenitors, highlighting the distinction between the lineage of cells in vivo and their potential when exposed to a different environment, e.g., in vitro. We then proceed to the adult stage and discuss the Glial cells that continue to act as NSCs across vertebrates and others that are more lineage-restricted, such as the adult NG2-Glia, the most frequent progenitor type in the adult mammalian brain, that remain within the oligodendrocyte lineage. Upon certain injury conditions, a distinct subset of quiescent astrocytes reactivates proliferation and a larger potential, clearly demonstrating the concept of heterogeneity with distinct subtypes of, e.g., astrocytes or NG2-Glia performing rather different roles after brain injury. These new insights not only highlight the importance of Glial cells for brain repair but also their great potential in various aspects of regeneration.
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progeny of olig2 expressing progenitors in the gray and white matter of the adult mouse cerebral cortex
The Journal of Neuroscience, 2008Co-Authors: Leda Dimou, Frank Kirchhoff, Christiane Simon, Hirohide Takebayashi, Magdalena GötzAbstract:Despite their abundance, still little is known about the rather frequent, constantly proliferating progenitors spread throughout the adult mouse brain parenchyma. The majority of these progenitors express the basic-helix-loop-helix transcription factor Olig2, and their number further increases after injury. Here, we examine the progeny of this progenitor population by genetic fate mapping using tamoxifen-inducible Cre-recombination in the Olig2 locus to turn on permanent reporter gene expression in the adult brain. Consistent with Olig2 expression in proliferating NG2+ progenitors, most reporter+ cells seen shortly after initiating recombination at adult stages incorporated BrdU and contained the proteoglycan NG2 in both the gray (GM) and the white matter (WM) of the cerebral cortex. However, at longer time points after induction, we observed profound differences in the identity of reporter+ cells in the WM and GM. Whereas most of the Olig2+ progenitors had generated mature, myelinating oligodendrocytes in the WM, hardly any reporter+ cells showing mature oligodendrocyte characteristics were detectable even up to 6 months after recombination in the GM. In the GM, most reporter+ cells remained NG2+, even after injury, but stopped proliferating rather soon after recombination. Thus, our results demonstrate the continuous generation of mature, myelinating oligodendrocytes in the WM, whereas cells in the GM generated mostly postmitotic NG2+ Glia.
Andrea Rivera - One of the best experts on this subject based on the ideXlab platform.
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disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of alzheimer s disease
Neurobiology of Aging, 2020Co-Authors: Ilaria Vanzulli, Andrea Rivera, Maria Papanikolaou, Irene Chacon Delarocha, Francesca Pieropan, Diego Gomeznicola, Alexei Verkhratsky, Jose J Rodriguez, Arthur M ButtAbstract:Abstract There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-Glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-β (Aβ) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.
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physiology of oligodendroGlia
Advances in Experimental Medicine and Biology, 2019Co-Authors: Arthur M Butt, Maria Papanikolaou, Andrea RiveraAbstract:Oligodendrocytes are the myelinating cells of the CNS, producing the insulating myelin sheath that facilitates rapid electrical conduction of axonal action potentials. Oligodendrocytes arise from oligodendrocyte progenitor cells (OPCs) under the control of multiple factors, including neurotransmitters and other neuron-derived factors. A significant population of OPCs persists in the adult CNS, where they are often referred to as NG2-Glia, because they are identified by their expression of the NG2 chondroitin sulphate proteoglycan (CSPG4). In the adult brain, the primary function of NG2-Glia is the life-long generation of oligodendrocytes to replace myelin lost through natural 'wear and tear' and pathology, as well as to provide new oligodendrocytes to myelinate new connections formed in response to new life experiences. NG2-Glia contact synapses and respond to neurotransmitters and potassium released during neuronal transmission; to this end, NG2-Glia (OPCs) express multiple neurotransmitter receptors and ion channels, with prominent roles being identified for glutamatergic signalling and potassium channels in oligodendrocyte differentiation. Myelinating oligodendrocytes also express a wide range of neurotransmitter receptors and ion channels, together with transporters and gap junctions; together, these have critical functions in cellular ion and water homeostasis, as well as metabolism, which is essential for maintaining myelin and axon integrity. An overriding theme is that oligodendrocyte function and myelination is not only essential for rapid axonal conduction, but is essential for learning and the long-term integrity of axons and neurones. Hence, myelination underpins cognitive function and the massive computing power of the human brain and myelin loss has devastating effects on CNS function. This chapter focuses on normal oligodendrocyte physiology.
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METHODS Immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan
2016Co-Authors: Giampaolo Leoni, Andrea Rivera, Marcus Rattray, Daniel Fulton, Arthur M ButtAbstract:Expression of the transmembrane NG2 chondroitin sulphate proteoglycan (CSPG) defines a distinct population of NG2-Glia. NG2-Glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system (CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the Glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-Glia form unique neuron–Glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-Glia in any of these functions using conventional transgenic NG2 ‘knockout ’ mice. To overcome this, we aimed to determine whether NG2-Glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti-NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-Glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-Glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration. Key words: Glia; immunoablation; immunotoxin; NG2 proteoglycan; oligodendrocyte progenitor cells; oligodendrocyte precursor cells
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decreased regenerative capacity of oligodendrocyte progenitor cells NG2 Glia in the ageing brain a vicious cycle of synaptic dysfunction myelin loss and neuronal disruption
Current Alzheimer Research, 2016Co-Authors: Andrea Rivera, Ilaria Vanzuli, Jose Julio Rodriguez Arellano, Arthur M ButtAbstract:Oligodendrocytes are specialised Glial cells that myelinate CNS axons. Myelinated axons are bundled together into white matter tracts that interconnect grey matter areas of the brain and are essential for rapid, integrated neuronal communication and cognitive function. Life-long generation of oligodendrocytes is required for myelination of new neuronal connections and repair of myelin lost through natural 'wear and tear'. This is the function of a substantial population of adult oligodendrocyte progenitors (OPs). Notably, there is white matter shrinkage and decreased myelination in the ageing brain, which is accelerated in dementia. The underlying causes of myelin loss in dementia are unresolved, but it implies a decline in the regenerative capacity of OPs. A feature of OPs is that they form neuron-Glial synapses and respond to glutamate released by neurons via a range of glutamate receptors. Glutamate neurotransmission onto OPs is proposed to regulate their proliferation and differentiation into myelinating oligodendrocytes. Here, we discuss evidence that deregulation of glutamate neurotransmission in dementia and compromised generation of oligodendrocytes from OPs are key features of myelin loss and associated cognitive decline.
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immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan
Journal of Anatomy, 2014Co-Authors: Giampaolo Leoni, Andrea Rivera, Marcus Rattray, Daniel Fulton, Arthur M ButtAbstract:Expression of the transmembrane NG2 chondroitin sulphate proteoglycan (CSPG) defines a distinct population of NG2-Glia. NG2-Glia serve as a regenerative pool of oligodendrocyte progenitor cells in the adult central nervous system (CNS), which is important for demyelinating diseases such as multiple sclerosis, and are a major component of the Glial scar that inhibits axon regeneration after CNS injury. In addition, NG2-Glia form unique neuron–Glial synapses with unresolved functions. However, to date it has proven difficult to study the importance of NG2-Glia in any of these functions using conventional transgenic NG2 ‘knockout’ mice. To overcome this, we aimed to determine whether NG2-Glia can be targeted using an immunotoxin approach. We demonstrate that incubation in primary anti-NG2 antibody in combination with secondary saporin-conjugated antibody selectively kills NG2-expressing cells in vitro. In addition, we provide evidence that the same protocol induces the loss of NG2-Glia without affecting astrocyte or neuronal numbers in cerebellar brain slices from postnatal mice. This study shows that targeting the NG2 CSPG with immunotoxins is an effective and selective means for killing NG2-Glia, which has important implications for studying the functions of these enigmatic cells both in the normal CNS, and in demyelination and degeneration.
Magdalena Götz - One of the best experts on this subject based on the ideXlab platform.
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influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex
Glia, 2018Co-Authors: Nicola Mattugini, Juliane Merlpham, Elisabetta Petrozziello, Lisa Schindler, Jurgen Bernhagen, Stefanie M Hauck, Magdalena GötzAbstract:Traumatic brain injury frequently affects the cerebral cortex, yet little is known about the differential effects that occur if only the gray matter (GM) is damaged or if the injury also involves the white matter (WM). To tackle this important question and directly compare similarities and differences in reactive gliosis, we performed stab wound injury affecting GM and WM (GM+) and one restricted to the GM (GM-) in the adult murine cerebral cortex. First, we examined Glial reactivity in the regions affected (WM and GM) and determined the influence of WM injury on reactive gliosis in the GM comparing the same area in the two injury paradigms. In the GM+ injury microGlia proliferation is increased in the WM compared with GM, while proliferating astrocytes are more abundant in the GM than in the WM. Interestingly, WM lesion exerted a strong influence on the proliferation of the GM Glial cells that was most pronounced at early stages, 3 days post lesion. While astrocyte proliferation was increased, NG2 Glia proliferation was decreased in the GM+ compared with GM- lesion condition. Importantly, these differences were not observed when a lesion of the same size affected only the GM. Unbiased proteomic analyses further corroborate our findings in support of a profound difference in GM reactivity when WM is also injured and revealed MIF as a key regulator of NG2 Glia proliferation.
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sox2 mediated conversion of NG2 Glia into induced neurons in the injured adult cerebral cortex
Stem cell reports, 2014Co-Authors: Christophe Heinrich, Leda Dimou, Matteo Bergami, Sergio Gascon, Alexandra Lepier, Francesca Vigano, Bernd Sutor, Benedikt Berninger, Magdalena GötzAbstract:The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 Glia into induced doublecortin (DCX)+ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroGlial and astroGlial cells into DCX+ cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 Glia represent a potential target for reprogramming strategies toward cortical repair.
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Glial cells as progenitors and stem cells new roles in the healthy and diseased brain
Physiological Reviews, 2014Co-Authors: Leda Dimou, Magdalena GötzAbstract:The diverse functions of Glial cells prompt the question to which extent specific subtypes may be devoted to a specific function. We discuss this by reviewing one of the most recently discovered roles of Glial cells, their function as neural stem cells (NSCs) and progenitor cells. First we give an overview of Glial stem and progenitor cells during development; these are the radial Glial cells that act as NSCs and other Glial progenitors, highlighting the distinction between the lineage of cells in vivo and their potential when exposed to a different environment, e.g., in vitro. We then proceed to the adult stage and discuss the Glial cells that continue to act as NSCs across vertebrates and others that are more lineage-restricted, such as the adult NG2-Glia, the most frequent progenitor type in the adult mammalian brain, that remain within the oligodendrocyte lineage. Upon certain injury conditions, a distinct subset of quiescent astrocytes reactivates proliferation and a larger potential, clearly demonstrating the concept of heterogeneity with distinct subtypes of, e.g., astrocytes or NG2-Glia performing rather different roles after brain injury. These new insights not only highlight the importance of Glial cells for brain repair but also their great potential in various aspects of regeneration.
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progeny of olig2 expressing progenitors in the gray and white matter of the adult mouse cerebral cortex
The Journal of Neuroscience, 2008Co-Authors: Leda Dimou, Frank Kirchhoff, Christiane Simon, Hirohide Takebayashi, Magdalena GötzAbstract:Despite their abundance, still little is known about the rather frequent, constantly proliferating progenitors spread throughout the adult mouse brain parenchyma. The majority of these progenitors express the basic-helix-loop-helix transcription factor Olig2, and their number further increases after injury. Here, we examine the progeny of this progenitor population by genetic fate mapping using tamoxifen-inducible Cre-recombination in the Olig2 locus to turn on permanent reporter gene expression in the adult brain. Consistent with Olig2 expression in proliferating NG2+ progenitors, most reporter+ cells seen shortly after initiating recombination at adult stages incorporated BrdU and contained the proteoglycan NG2 in both the gray (GM) and the white matter (WM) of the cerebral cortex. However, at longer time points after induction, we observed profound differences in the identity of reporter+ cells in the WM and GM. Whereas most of the Olig2+ progenitors had generated mature, myelinating oligodendrocytes in the WM, hardly any reporter+ cells showing mature oligodendrocyte characteristics were detectable even up to 6 months after recombination in the GM. In the GM, most reporter+ cells remained NG2+, even after injury, but stopped proliferating rather soon after recombination. Thus, our results demonstrate the continuous generation of mature, myelinating oligodendrocytes in the WM, whereas cells in the GM generated mostly postmitotic NG2+ Glia.
Akiko Nishiyama - One of the best experts on this subject based on the ideXlab platform.
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sequential contribution of parenchymal and neural stem cell derived oligodendrocyte precursor cells toward remyelination
Neuroglia (Basel Switzerland), 2018Co-Authors: David R Serwanski, Andrew L Rasmussen, Christopher B Brunquell, Scott S Perkins, Akiko NishiyamaAbstract:In the adult mammalian forebrain, oligodendrocyte precursor cells (OPCs), also known as NG2 Glia are distributed ubiquitously throughout the gray and white matter. They remain proliferative and continuously generate myelinating oligodendrocytes throughout life. In response to a demyelinating insult, OPCs proliferate rapidly and differentiate into oligodendrocytes which contribute to myelin repair. In addition to OPCs, neural stem cells (NSCs) in the subventricular zone (SVZ) also contribute to remyelinating oligodendrocytes, particularly in demyelinated lesions in the vicinity of the SVZ, such as the corpus callosum. To determine the relative contribution of local OPCs and NSC-derived cells toward myelin repair, we performed genetic fate mapping of OPCs and NSCs and compared their ability to generate oligodendrocytes after acute demyelination in the corpus callosum created by local injection of α-lysophosphatidylcholine (LPC). We have found that local OPCs responded rapidly to acute demyelination, expanded in the lesion within seven days, and produced oligodendrocytes by two weeks after lesioning. By contrast, NSC-derived NG2 cells did not significantly increase in the lesion until four weeks after demyelination and generated fewer oligodendrocytes than parenchymal OPCs. These observations suggest that local OPCs could function as the primary responders to repair acutely demyelinated lesion, and that NSCs in the SVZ contribute to repopulating OPCs following their depletion due to oligodendrocyte differentiation.
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NG2 cells generate both oligodendrocytes and gray matter astrocytes
Development, 2007Co-Authors: Dwight E Bergles, Akiko NishiyamaAbstract:NG2 Glia constitute a fourth major Glial cell type in the mammalian central nervous system (CNS) that is distinct from other cell types. Although circumstantial evidence suggests that some NG2 Glia differentiate into oligodendrocytes, their in vivo fate has not been directly examined. We have used the bacterial artificial chromosome (BAC) modification technique to generate transgenic mice that express DsRed or Cre specifically in NG2-expressing (NG2+) cells. In NG2DsRedBAC transgenic mice, DsRed was expressed specifically in NG2+ cells throughout the postnatal CNS. When the differentiation potential of NG2+ cells in vitro was examined using DsRed+NG2+ cells purified from perinatal transgenic brains, the majority of the cells either remained as NG2+ cells or differentiated into oligodendrocytes. In addition, DsRed+NG2+ cells also differentiated into astrocytes. The in vivo fate of NG2 Glia was examined in mice that were double transgenic for NG2creBAC and the Cre reporter Z/EG. In the double transgenic mice, the Cre reporter EGFP was detected in myelinating oligodendrocytes and in a subpopulation of protoplasmic astrocytes in the gray matter of ventrolateral forebrain but not in fibrous astrocytes of white matter. These observations suggest that NG2+ cells are precursors of oligodendrocytes and some protoplasmic astrocytes in gray matter.
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vesicular release of glutamate from unmyelinated axons in white matter
Nature Neuroscience, 2007Co-Authors: Jennifer L Ziskin, Akiko Nishiyama, Maria E Rubio, Masahiro Fukaya, Dwight E BerglesAbstract:Directed fusion of transmitter-laden vesicles enables rapid intercellular signaling in the central nervous system and occurs at synapses within gray matter. Here we show that action potentials also induce the release of glutamate from axons in the corpus callosum, a white matter region responsible for interhemispheric communication. Callosal axons release glutamate by vesicular fusion, which induces quantal AMPA receptor–mediated currents in NG2+ Glial progenitors at anatomically distinct axo–Glial synaptic junctions. Glutamate release from axons was facilitated by repetitive stimulation and could be inhibited through activation of metabotropic autoreceptors. Although NG2+ cells form associations with nodes of Ranvier in white matter, measurements of conduction velocity indicated that unmyelinated fibers are responsible for glutamatergic signaling with NG2+ Glia. This activity-dependent secretion of glutamate was prevalent in the developing and mature mouse corpus callosum, indicating that axons within white matter both conduct action potentials and engage in rapid neuron-Glia communication.
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optimization of oligodendrocyte progenitor cell culture method for enhanced survival
Journal of Neuroscience Methods, 2005Co-Authors: Zhongshu Yang, Masahiko Watanabe, Akiko NishiyamaAbstract:Oligodendrocyte progenitor cells (OPCs, NG2 Glia) play an important role not only as progenitor cells that give rise to myelinating cells in the central nervous system (CNS), but also as an active participant in the neural network. It is necessary to develop a simplified method for generating large quantities of highly purified OPCs for biochemical studies and to establish a neuron-OPC coculture method for functional studies on the mechanism of neuron-OPC signaling. In this study, we have compared the effects of plating density and culture medium on purity, survival, and differentiation of cells collected from primary rat mixed Glial cultures by differential adhesion. Comparison of two chemically-defined culture media, Dulbecco's modified Eagle's medium with N1 supplements (N1/DMEM) and Neurobasal medium with B27 supplements (B27/NBM) revealed that while both media successfully maintained greater than 90% pure OPCs after 3 days, B27/NBM was significantly more effective in maintaining viable cells and in supporting oligodendrocyte differentiation than N1/DMEM, and this effect was more pronounced in low density cultures. Furthermore, B27/NBM supported neuron-OPC coculture in which OPCs remained as NG2-positive progenitors and neurons differentiated to form synapses over a period of 3 weeks.