The Experts below are selected from a list of 93 Experts worldwide ranked by ideXlab platform
Steven A Goldman - One of the best experts on this subject based on the ideXlab platform.
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a competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia
The Journal of Neuroscience, 2014Co-Authors: Martha S Windrem, Stevenj . Schanz, Carolyn Morrow, Jared Munir, Devin Chandlermilitello, Su Wang, Steven A GoldmanAbstract:Neonatally transplanted human glial progenitor cells (hGPCs) densely engraft and myelinate the hypomyelinated Shiverer Mouse. We found that, in hGPC-xenografted mice, the human donor cells continue to expand throughout the forebrain, systematically replacing the host murine glia. The differentiation of the donor cells is influenced by the host environment, such that more donor cells differentiated as oligodendrocytes in the hypomyelinated Shiverer brain than in myelin wild-types, in which hGPCs were more likely to remain as progenitors. Yet in each recipient, both the number and relative proportion of Mouse GPCs fell as a function of time, concomitant with the mitotic expansion and spread of donor hGPCs. By a year after neonatal xenograft, the forebrain GPC populations of implanted mice were largely, and often entirely, of human origin. Thus, neonatally implanted hGPCs outcompeted and ultimately replaced the host population of Mouse GPCs, ultimately generating mice with a humanized glial progenitor population. These human glial chimeric mice should permit us to define the specific contributions of glia to a broad variety of neurological disorders, using human cells in vivo.
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cd140a identifies a population of highly myelinogenic migration competent and efficiently engrafting human oligodendrocyte progenitor cells
Nature Biotechnology, 2011Co-Authors: Fraser J. Sim, Stevenj . Schanz, Martha S Windrem, Crystal R Mcclain, Tricia L Protack, Steven A GoldmanAbstract:Experimental animals with myelin disorders can be treated by transplanting oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs have been isolated by their expression of gangliosides recognized by mAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we sorted fetal human forebrain cells for CD140a, an epitope of platelet derived growth factor receptor (PDGFR)α, which is differentially expressed by OPCs. CD140a(+) cells were isolated as mitotic bipotential progenitors that initially expressed neither mature neuronal nor astrocytic phenotypic markers, yet could be instructed to either oligodendrocyte or astrocyte fate in vitro. Transplanted CD140a(+) cells were highly migratory and robustly myelinated the hypomyelinated Shiverer Mouse brain more rapidly and efficiently than did A2B5(+)cells. Microarray analysis of CD140a(+) cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9(+)/CD140a(+) cells may constitute an even more highly enriched population of myelinogenic progenitor cells.
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neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated Shiverer Mouse
Cell Stem Cell, 2008Co-Authors: Martha S Windrem, Stevenj . Schanz, Su Wang, Guofeng Tian, Vaughn Washco, Nancy L Stanwood, Matthew N Rasband, Leif A Havton, Steven A GoldmanAbstract:Summary Congenitally hypomyelinated Shiverer mice fail to generate compact myelin and die by 18–21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal Shiverer × rag2 −/− mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
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fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain
Nature Medicine, 2004Co-Authors: Martha S Windrem, Steven A Goldman, Marta Nunes, William K Rashbaum, Theodore H Schwartz, Robert A Goodman, Guy M Mckhann, Neeta S RoyAbstract:Both late-gestation and adult human forebrain contain large numbers of oligodendrocyte progenitor cells (OPCs). These cells may be identified by their A2B5+PSA-NCAM− phenotype (positive for the early oligodendrocyte marker A2B5 and negative for the polysialylated neural cell adhesion molecule). We used dual-color fluorescence-activated cell sorting (FACS) to extract OPCs from 21- to 23-week-old fetal human forebrain, and A2B5 selection to extract these cells from adult white matter. When xenografted to the forebrains of newborn Shiverer mice, fetal OPCs dispersed throughout the white matter and developed into oligodendrocytes and astrocytes. By 12 weeks, the host brains showed extensive myelin production, compaction and axonal myelination. Isolates of OPCs derived from adult human white matter also myelinated Shiverer Mouse brain, but much more rapidly than their fetal counterparts, achieving widespread and dense myelin basic protein (MBP) expression by 4 weeks after grafting. Adult OPCs generated oligodendrocytes more efficiently than fetal OPCs, and ensheathed more host axons per donor cell than fetal cells. Both fetal and adult OPC phenotypes mediated the extensive and robust myelination of congenitally dysmyelinated host brain, although their differences suggested their use for different disease targets.
Martha S Windrem - One of the best experts on this subject based on the ideXlab platform.
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a competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia
The Journal of Neuroscience, 2014Co-Authors: Martha S Windrem, Stevenj . Schanz, Carolyn Morrow, Jared Munir, Devin Chandlermilitello, Su Wang, Steven A GoldmanAbstract:Neonatally transplanted human glial progenitor cells (hGPCs) densely engraft and myelinate the hypomyelinated Shiverer Mouse. We found that, in hGPC-xenografted mice, the human donor cells continue to expand throughout the forebrain, systematically replacing the host murine glia. The differentiation of the donor cells is influenced by the host environment, such that more donor cells differentiated as oligodendrocytes in the hypomyelinated Shiverer brain than in myelin wild-types, in which hGPCs were more likely to remain as progenitors. Yet in each recipient, both the number and relative proportion of Mouse GPCs fell as a function of time, concomitant with the mitotic expansion and spread of donor hGPCs. By a year after neonatal xenograft, the forebrain GPC populations of implanted mice were largely, and often entirely, of human origin. Thus, neonatally implanted hGPCs outcompeted and ultimately replaced the host population of Mouse GPCs, ultimately generating mice with a humanized glial progenitor population. These human glial chimeric mice should permit us to define the specific contributions of glia to a broad variety of neurological disorders, using human cells in vivo.
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cd140a identifies a population of highly myelinogenic migration competent and efficiently engrafting human oligodendrocyte progenitor cells
Nature Biotechnology, 2011Co-Authors: Fraser J. Sim, Stevenj . Schanz, Martha S Windrem, Crystal R Mcclain, Tricia L Protack, Steven A GoldmanAbstract:Experimental animals with myelin disorders can be treated by transplanting oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs have been isolated by their expression of gangliosides recognized by mAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we sorted fetal human forebrain cells for CD140a, an epitope of platelet derived growth factor receptor (PDGFR)α, which is differentially expressed by OPCs. CD140a(+) cells were isolated as mitotic bipotential progenitors that initially expressed neither mature neuronal nor astrocytic phenotypic markers, yet could be instructed to either oligodendrocyte or astrocyte fate in vitro. Transplanted CD140a(+) cells were highly migratory and robustly myelinated the hypomyelinated Shiverer Mouse brain more rapidly and efficiently than did A2B5(+)cells. Microarray analysis of CD140a(+) cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9(+)/CD140a(+) cells may constitute an even more highly enriched population of myelinogenic progenitor cells.
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neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated Shiverer Mouse
Cell Stem Cell, 2008Co-Authors: Martha S Windrem, Stevenj . Schanz, Su Wang, Guofeng Tian, Vaughn Washco, Nancy L Stanwood, Matthew N Rasband, Leif A Havton, Steven A GoldmanAbstract:Summary Congenitally hypomyelinated Shiverer mice fail to generate compact myelin and die by 18–21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal Shiverer × rag2 −/− mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
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fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain
Nature Medicine, 2004Co-Authors: Martha S Windrem, Steven A Goldman, Marta Nunes, William K Rashbaum, Theodore H Schwartz, Robert A Goodman, Guy M Mckhann, Neeta S RoyAbstract:Both late-gestation and adult human forebrain contain large numbers of oligodendrocyte progenitor cells (OPCs). These cells may be identified by their A2B5+PSA-NCAM− phenotype (positive for the early oligodendrocyte marker A2B5 and negative for the polysialylated neural cell adhesion molecule). We used dual-color fluorescence-activated cell sorting (FACS) to extract OPCs from 21- to 23-week-old fetal human forebrain, and A2B5 selection to extract these cells from adult white matter. When xenografted to the forebrains of newborn Shiverer mice, fetal OPCs dispersed throughout the white matter and developed into oligodendrocytes and astrocytes. By 12 weeks, the host brains showed extensive myelin production, compaction and axonal myelination. Isolates of OPCs derived from adult human white matter also myelinated Shiverer Mouse brain, but much more rapidly than their fetal counterparts, achieving widespread and dense myelin basic protein (MBP) expression by 4 weeks after grafting. Adult OPCs generated oligodendrocytes more efficiently than fetal OPCs, and ensheathed more host axons per donor cell than fetal cells. Both fetal and adult OPC phenotypes mediated the extensive and robust myelination of congenitally dysmyelinated host brain, although their differences suggested their use for different disease targets.
Michel Brahic - One of the best experts on this subject based on the ideXlab platform.
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The Role of Myelin in Theiler’s Virus Persistence in the Central Nervous System
2013Co-Authors: Jean-pierre Roussarie, Claude Ruffié, Michel BrahicAbstract:Theiler’s virus, a picornavirus, persists for life in the central nervous system of Mouse and causes a demyelinating disease that is a model for multiple sclerosis. The virus infects neurons first but persists in white matter glial cells, mainly oligodendrocytes and macrophages. The mechanism, by which the virus traffics from neurons to glial cells, and the respective roles of oligodendrocytes and macrophages in persistence are poorly understood. We took advantage of our previous finding that the Shiverer Mouse, a mutant with a deletion in the myelin basic protein gene (Mbp), is resistant to persistent infection to examine the role of myelin in persistence. Using immune chimeras, we show that resistance is not mediated by immune responses or by an efficient recruitment of inflammatory cells into the central nervous system. With both in vivo and in vitro experiments, we show that the mutation does not impair the permissiveness of neurons, oligodendrocytes, and macrophages to the virus. We demonstrate that viral antigens are present in cytoplasmic channels of myelin during persistent infection of wild-type mice. Using the optic nerve as a model, we show that the virus traffics from the axons of retinal ganglion cells to the cytoplasmic channels of myelin, and that this traffic is impaired by the Shiverer mutation. These results uncover an unsuspected axon to myelin traffic of Theiler’s virus and the essential role played by the infection of myelin/oligodendrocyte in persistence. Citation: Roussarie JP, Ruffié C, Brahic M (2007) The role of myelin in Theiler’s virus persistence in the central nervous system. PLoS Pathog 3(2): e23. doi:10.1371/journal.ppat
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Axon myelin transfer of a non-enveloped virus.
PLoS ONE, 2007Co-Authors: Jean-pierre Roussarie, Julia M. Edgar, Ian R. Griffiths, Claude Ruffié, Michel BrahicAbstract:We showed previously that Theiler's virus, a neurotropic non-enveloped picornavirus of Mouse, traffics from the axon of infected neurons into the surrounding myelin. When this traffic is interrupted, as in the Shiverer Mouse which bears a mutation in the myelin basic protein gene, the virus is unable to persist in the central nervous system. In the present work, we used the Wlds mutant Mouse, a strain in which axonal degeneration is considerably slowed down, to show that axon to myelin traffic takes place in the absence of axon degeneration. Our results suggest the existence of a mechanism of transfer of axonal cytoplasm into the myelin which Theiler's virus might exploit to ensure its persistence.
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The Role of Myelin in Theiler's Virus Persistence in the Central Nervous System
PLoS Pathogens, 2007Co-Authors: Jean-pierre Roussarie, Claude Ruffié, Michel BrahicAbstract:Theiler's virus, a picornavirus, persists for life in the central nervous system of Mouse and causes a demyelinating disease that is a model for multiple sclerosis. The virus infects neurons first but persists in white matter glial cells, mainly oligodendrocytes and macrophages. The mechanism, by which the virus traffics from neurons to glial cells, and the respective roles of oligodendrocytes and macrophages in persistence are poorly understood. We took advantage of our previous finding that the Shiverer Mouse, a mutant with a deletion in the myelin basic protein gene (Mbp), is resistant to persistent infection to examine the role of myelin in persistence. Using immune chimeras, we show that resistance is not mediated by immune responses or by an efficient recruitment of inflammatory cells into the central nervous system. With both in vivo and in vitro experiments, we show that the mutation does not impair the permissiveness of neurons, oligodendrocytes, and macrophages to the virus. We demonstrate that viral antigens are present in cytoplasmic channels of myelin during persistent infection of wild-type mice. Using the optic nerve as a model, we show that the virus traffics from the axons of retinal ganglion cells to the cytoplasmic channels of myelin, and that this traffic is impaired by the Shiverer mutation. These results uncover an unsuspected axon to myelin traffic of Theiler's virus and the essential role played by the infection of myelin/oligodendrocyte in persistence.
Stevenj . Schanz - One of the best experts on this subject based on the ideXlab platform.
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a competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia
The Journal of Neuroscience, 2014Co-Authors: Martha S Windrem, Stevenj . Schanz, Carolyn Morrow, Jared Munir, Devin Chandlermilitello, Su Wang, Steven A GoldmanAbstract:Neonatally transplanted human glial progenitor cells (hGPCs) densely engraft and myelinate the hypomyelinated Shiverer Mouse. We found that, in hGPC-xenografted mice, the human donor cells continue to expand throughout the forebrain, systematically replacing the host murine glia. The differentiation of the donor cells is influenced by the host environment, such that more donor cells differentiated as oligodendrocytes in the hypomyelinated Shiverer brain than in myelin wild-types, in which hGPCs were more likely to remain as progenitors. Yet in each recipient, both the number and relative proportion of Mouse GPCs fell as a function of time, concomitant with the mitotic expansion and spread of donor hGPCs. By a year after neonatal xenograft, the forebrain GPC populations of implanted mice were largely, and often entirely, of human origin. Thus, neonatally implanted hGPCs outcompeted and ultimately replaced the host population of Mouse GPCs, ultimately generating mice with a humanized glial progenitor population. These human glial chimeric mice should permit us to define the specific contributions of glia to a broad variety of neurological disorders, using human cells in vivo.
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cd140a identifies a population of highly myelinogenic migration competent and efficiently engrafting human oligodendrocyte progenitor cells
Nature Biotechnology, 2011Co-Authors: Fraser J. Sim, Stevenj . Schanz, Martha S Windrem, Crystal R Mcclain, Tricia L Protack, Steven A GoldmanAbstract:Experimental animals with myelin disorders can be treated by transplanting oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs have been isolated by their expression of gangliosides recognized by mAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we sorted fetal human forebrain cells for CD140a, an epitope of platelet derived growth factor receptor (PDGFR)α, which is differentially expressed by OPCs. CD140a(+) cells were isolated as mitotic bipotential progenitors that initially expressed neither mature neuronal nor astrocytic phenotypic markers, yet could be instructed to either oligodendrocyte or astrocyte fate in vitro. Transplanted CD140a(+) cells were highly migratory and robustly myelinated the hypomyelinated Shiverer Mouse brain more rapidly and efficiently than did A2B5(+)cells. Microarray analysis of CD140a(+) cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9(+)/CD140a(+) cells may constitute an even more highly enriched population of myelinogenic progenitor cells.
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neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated Shiverer Mouse
Cell Stem Cell, 2008Co-Authors: Martha S Windrem, Stevenj . Schanz, Su Wang, Guofeng Tian, Vaughn Washco, Nancy L Stanwood, Matthew N Rasband, Leif A Havton, Steven A GoldmanAbstract:Summary Congenitally hypomyelinated Shiverer mice fail to generate compact myelin and die by 18–21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal Shiverer × rag2 −/− mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.
Marlis Ontivero Ortega - One of the best experts on this subject based on the ideXlab platform.
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Automated Discrimination of Brain Pathological State Attending to Complex Structural Brain Network Properties: The Shiverer Mutant Mouse Case
2013Co-Authors: Yasser Iturria-medina, Ro Pérez Fernández, Pedro Valdés Hernández, Lorna García Pentón, Erick J. Canales-rodríguez, Lester Melie-garcia, Agustin Lage Castellanos, Marlis Ontivero OrtegaAbstract:Neuroimaging classification procedures between normal and pathological subjects are sparse and highly dependent of an expert’s clinical criterion. Here, we aimed to investigate whether possible brain structural network differences in the Shiverer Mouse mutant, a relevant animal model of myelin related diseases, can reflect intrinsic individual brain properties that allow the automatic discrimination between the Shiverer and normal subjects. Common structural networks properties between Shiverer (C3Fe.SWV Mbp shi /Mbp shi, n = 6) and background control (C3HeB.FeJ, n = 6) mice are estimated and compared by means of three diffusion weighted MRI (DW-MRI) fiber tractography algorithms and a graph framework. Firstly, we found that brain networks of control group are significantly more clustered, modularized, efficient and optimized than those of the Shiverer group, which presented significantly increased characteristic path length. These results are in line with previous structural/functional complex brain networks analysis that have revealed topologic differences and brain network randomization associated to specific states of human brain pathology. In addition, by means of network measures spatial representations and discrimination analysis, we show that it is possible to classify with high accuracy to which group each subject belongs, providing also a probability value of being a normal or Shiverer subject as an individual anatomica
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Automated Discrimination of Brain Pathological State Attending to Complex Structural Brain Network Properties: The Shiverer Mutant Mouse Case
PLoS ONE, 2011Co-Authors: Yasser Iturria-medina, Pedro Valdés Hernández, Lorna García Pentón, Erick J. Canales-rodríguez, Lester Melie-garcia, Agustin Lage Castellanos, Alejandro Pérez Fernández, Marlis Ontivero OrtegaAbstract:Neuroimaging classification procedures between normal and pathological subjects are sparse and highly dependent of an expert's clinical criterion. Here, we aimed to investigate whether possible brain structural network differences in the Shiverer Mouse mutant, a relevant animal model of myelin related diseases, can reflect intrinsic individual brain properties that allow the automatic discrimination between the Shiverer and normal subjects. Common structural networks properties between Shiverer (C3Fe.SWV Mbp(shi)/Mbp(shi), n = 6) and background control (C3HeB.FeJ, n = 6) mice are estimated and compared by means of three diffusion weighted MRI (DW-MRI) fiber tractography algorithms and a graph framework. Firstly, we found that brain networks of control group are significantly more clustered, modularized, efficient and optimized than those of the Shiverer group, which presented significantly increased characteristic path length. These results are in line with previous structural/functional complex brain networks analysis that have revealed topologic differences and brain network randomization associated to specific states of human brain pathology. In addition, by means of network measures spatial representations and discrimination analysis, we show that it is possible to classify with high accuracy to which group each subject belongs, providing also a probability value of being a normal or Shiverer subject as an individual anatomical classifier. The obtained correct predictions (e.g., around 91.6-100%) and clear spatial subdivisions between control and Shiverer mice, suggest that there might exist specific network subspaces corresponding to specific brain disorders, supporting also the point of view that complex brain network analyses constitutes promising tools in the future creation of interpretable imaging biomarkers.