The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Mark Noble - One of the best experts on this subject based on the ideXlab platform.
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Oligodendrocyte/Type-2 Astrocyte Progenitor Cells and Glial-Restricted Precursor Cells Generate Different Tumor PhenoTypes in Response to the Identical Oncogenes
The Journal of Neuroscience, 2013Co-Authors: Jun Wang, Jared Bushman, Xi Wang, Mahlon D Johnson, Margot Mayer-pröschel, Mark NobleAbstract:Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two Types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/Type-2 Astrocyte progenitor cells (O-2A/OPCs), and in Astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU. In vivo, cells differed in their ability to form tumors, in malignancy and even in the Type of host-derived cells infiltrating the tumor mass. Moreover, identical genetic modification of these different cells yielded benign infiltrative astrocytomas, malignant astrocytomas, or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas, indicating a contribution of cell-of-origin to the characteristic properties expressed by these different tumors. Our studies also revealed unexpected relationships between the cell-of-origin, differentiation, and the order of oncogene acquisition at different developmental stages in enabling neoplastic growth. These studies thus provide multiple novel demonstrations of the importance of the cell-of-origin in respect to the properties of transformed cells derived from them. In addition, the approaches used enable analysis of the role of cell-of-origin in tumor biology in ways that are not accessible by other more widely used approaches.
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oligodendrocyte Type 2 Astrocyte progenitor cells and glial restricted precursor cells generate different tumor phenoTypes in response to the identical oncogenes
The Journal of Neuroscience, 2013Co-Authors: Jun Wang, Margot Mayerproschel, Jared Bushman, Xi Wang, Mahlon D Johnson, Mark NobleAbstract:Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two Types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/Type-2 Astrocyte progenitor cells (O-2A/OPCs), and in Astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU. In vivo, cells differed in their ability to form tumors, in malignancy and even in the Type of host-derived cells infiltrating the tumor mass. Moreover, identical genetic modification of these different cells yielded benign infiltrative astrocytomas, malignant astrocytomas, or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas, indicating a contribution of cell-of-origin to the characteristic properties expressed by these different tumors. Our studies also revealed unexpected relationships between the cell-of-origin, differentiation, and the order of oncogene acquisition at different developmental stages in enabling neoplastic growth. These studies thus provide multiple novel demonstrations of the importance of the cell-of-origin in respect to the properties of transformed cells derived from them. In addition, the approaches used enable analysis of the role of cell-of-origin in tumor biology in ways that are not accessible by other more widely used approaches.
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Ciba Foundation Symposium 150 - Proto-Oncogenes in Cell Development - Control of Division and Differentiation in Oligodendrocyte‐Type‐2 Astrocyte Progenitor Cells
Ciba Foundation symposium, 2007Co-Authors: Mark Noble, Susan C Barnett, Oliver Bogler, Hartmut Land, Guus Wolswijk, Damian WrenAbstract:Oligodendrocyte-Type-2 Astrocyte (O-2A) progenitor cells give rise to oligodendrocytes and Type-2 Astrocytes in cultures of rat optic nerve. These progenitors are one of the few cell Types in which most aspects of proliferation and differentiation can be manipulated in a defined in vitro environment. When exposed to platelet-derived growth factor (PDGF), O-2A progenitors divide a limited number of times before clonally related cells differentiate into oligodendrocytes with a timing similar to that seen in vivo. In contrast, O-2A progenitors grown in the absence of mitogen do not divide but differentiate prematurely into oligodendrocytes, and progenitors exposed to appropriate inducing factors differentiate into Type-2 Astrocytes. O-2A progenitors can become immortalized through at least two different mechanisms. First, when O-2A progenitors are exposed to a combination of PDGF and basic fibroblast growth factor (bFGF) these cells undergo continuous self-renewal in the absence of differentiation. In contrast, the application of bFGF alone is associated with premature oligodendrocytic differentiation of dividing O-2A lineage cells. Thus, cooperation between growth factors can modulate O-2A progenitor self-renewal in a defined chemical environment by eliciting a novel programme of division and differentiation which cannot be predicted from the effects of either factor examined in isolation. A further mechanism which allows prolonged self-renewal in the O-2A lineage is the generation of a stem cell. O-2A progenitors isolated from optic nerves of perinatal rats also have the capacity to give rise to a population of cells called O-2Aadult progenitors, which differ from their perinatal counterparts in many characteristics. Most importantly, O-2Aadult progenitors have a slow cell cycle, divide and differentiate asymmetrically and appear to have the capacity for prolonged self-renewal. Thus, immortalization in this lineage can also be achieved by the generation of a cell with stem cell-like characteristics from a rapidly dividing progenitor population.
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the tripotential glial restricted precursor grp cell and glial development in the spinal cord generation of bipotential oligodendrocyte Type 2 Astrocyte progenitor cells and dorsal ventral differences in grp cell function
The Journal of Neuroscience, 2002Co-Authors: Ninel Z Gregori, Mark Noble, Christoph Proschel, Margot MayerproschelAbstract:We have found that the tripotential glial-restricted precursor (GRP) cell of the embryonic rat spinal cord can give rise in vitro to bipotential cells that express defining characteristics of oligodendrocyte-Type-2 Astrocyte progenitor cells (O2A/OPCs). Generation of O2A/OPCs is regulated by environmental signals and is promoted by platelet-derived growth factor (PDGF), thyroid hormone (TH) and Astrocyte-conditioned medium. In contrast to multiple observations indicating that oligodendrocyte precursor cells in the embryonic day 14 (E14) spinal cord are ventrally restricted, GRP cells are already present in both the dorsal and ventral spinal cord at E13.5. Ventral-derived GRP cells, however, were more likely to generate O2A/OPCs and/or oligodendrocytes than were their dorsal counterparts when exposed to TH, PDGF, or even bone morphogenetic protein-4. The simplest explanation of our results is that oligodendrocyte generation occurs as a result of generation of GRP cells from totipotent neuroepithelial stem cells, of O2A/OPCs from GRP cells and, finally, of oligodendrocytes from O2A/OPCs. In this respect, the responsiveness of GRP cells to modulators of this process may represent a central control point in the initiation of this critical developmental sequence. Our findings provide an integration between the earliest known glial precursors and the well-studied O2A/OPCs while opening up new questions concerning the intricate spatial and temporal regulation of precursor cell differentiation in the CNS.
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alleletyping of an oligodendrocyte Type 2 Astrocyte lineage derive from a human glioblastoma multiforme
Journal of Neuro-oncology, 1998Co-Authors: Rita Barfoot, Rifat Hamoudi, Mark NobleAbstract:We have conducted alleletyping of two novel cell lines derived from glioblastoma multiforme, which appear to have arisen from different glial lineages, by using 76 fluorescently labeled oligonucleotide primers amplifying microsatellite loci covering the entire human genome. One cell line, Hu-O-2A/Gb1, expresses antigens and metabolic profiles characteristic of the oligodendrocyte-Type-2 Astrocyte (0-2A) lineage of the rat central nervous system. This cell line generated, in vitro, cells with characteristics of 0-2A progenitor cells, oligodendrocytes and Astrocytes. The second cell line, IN1434, is derived from an Astrocyte or a precursor cell restricted to astrocytic differentiation. Hu-O-2A/Gb1 cells show allelic losses of loci on chromosomes 2, 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, 17, 20 and 21. IN1434 cells are likely to have allelic losses of loci on chromosomes 1, 3, 8 and 10, although no control DNA is available for this cell line. These results, for the first time, provide a detailed information of the molecular genetic defects occurring in Hu-O-2A/Gb1 and IN1434.
Yuanyi Chang - One of the best experts on this subject based on the ideXlab platform.
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activation of p2x7 purinoceptor stimulated tgf β1 mrna expression involves pkc mapk signalling pathway in a rat brain derived Type 2 Astrocyte cell line rba 2
Cellular Signalling, 2003Co-Authors: Chiamei Wang, Yuanyi ChangAbstract:The present study investigates the receptor and mechanisms involved in ATP-stimulated transforming growth factor-beta 1 (TGF-β1) mRNA expression of a Type-2 Astrocyte cell line, RBA-2. RT-PCR analysis revealed that RBA-2 Type-2 Astrocytes possess abundant P2X4 and P2X7 receptors. ATP and P2X7 receptor-sensitive agonist, BzATP, both stimulated TGF-β1 mRNA expression in a time and dose-dependent manner. The stimulation required a minimum of 500 μM ATP; BzATP was much more potent that ATP, and P2X7-selective antagonist, oATP, inhibited the effects. In addition, ATP metabolites ADP, AMP and adenosine were ineffective in stimulation of TGF-β1 mRNA expression. Thus, the effect of ATP was mediated through the P2X7 receptors. To investigate further the mechanisms by which the P2X7 receptor mediated the TGF-β1 mRNA expression, the cells were treated with inhibitors for mitogen-activated kinase (MAPK) or protein kinase C (PKC), PD98059 or GF109203X, respectively. Both PD98059 and GF109203X inhibited the ATP-stimulated TGF-β1 mRNA expression. Furthermore, ATP and BzATP stimulated ERK1/2 activation and the activation was inhibited by PKC inhibitors, GF109203X and Go6976. In conclusion, activation of P2X7 receptors enhanced TGF-β1 mRNA expression and the effect involved PKC/MAPK signalling pathway in RBA-2 Type-2 Astrocytes.
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Activation of P2X7 purinoceptor-stimulated TGF-β1 mRNA expression involves PKC/MAPK signalling pathway in a rat brain-derived Type-2 Astrocyte cell line, RBA-2
Cellular Signalling, 2003Co-Authors: Chiamei Wang, Yuanyi ChangAbstract:The present study investigates the receptor and mechanisms involved in ATP-stimulated transforming growth factor-beta 1 (TGF-β1) mRNA expression of a Type-2 Astrocyte cell line, RBA-2. RT-PCR analysis revealed that RBA-2 Type-2 Astrocytes possess abundant P2X4 and P2X7 receptors. ATP and P2X7 receptor-sensitive agonist, BzATP, both stimulated TGF-β1 mRNA expression in a time and dose-dependent manner. The stimulation required a minimum of 500 μM ATP; BzATP was much more potent that ATP, and P2X7-selective antagonist, oATP, inhibited the effects. In addition, ATP metabolites ADP, AMP and adenosine were ineffective in stimulation of TGF-β1 mRNA expression. Thus, the effect of ATP was mediated through the P2X7 receptors. To investigate further the mechanisms by which the P2X7 receptor mediated the TGF-β1 mRNA expression, the cells were treated with inhibitors for mitogen-activated kinase (MAPK) or protein kinase C (PKC), PD98059 or GF109203X, respectively. Both PD98059 and GF109203X inhibited the ATP-stimulated TGF-β1 mRNA expression. Furthermore, ATP and BzATP stimulated ERK1/2 activation and the activation was inhibited by PKC inhibitors, GF109203X and Go6976. In conclusion, activation of P2X7 receptors enhanced TGF-β1 mRNA expression and the effect involved PKC/MAPK signalling pathway in RBA-2 Type-2 Astrocytes.
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activation of p2x7 receptors induced 3h gaba release from the rba 2 Type 2 Astrocyte cell line through a cl hco3 dependent mechanism
Glia, 2002Co-Authors: Chiamei Wang, Yuanyi ChangAbstract:: ATP is an important signaling molecule in the nervous system and it's signaling is mediated through the metabotropic P2Y and ionotropic P2X receptors. ATP is known to stimulate Ca(2+) influx and phospholipase D (PLD) activity in the Type-2 Astrocyte cell line, RBA-2; in this study, we show that the release of preloaded [(3)H]GABA from RBA-2 cells is mediated through the P2X(7) receptors. ATP and the ATP analogue 3'-O-(4-benoylbenoyl)-adenosine-5'-triphosphate (BzATP) both stimulated [(3)H]GABA release in a concentration dependent manner, while the nonselective P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), the P2X(7)-sensitive antagonist oxidized ATP (oATP), and high extracellular Mg(2+) all inhibited the ATP-stimulated [(3)H]GABA release. The ATP-stimulated [(3)H]GABA release was not affected neither by removing extracellular Na(+) nor by changes in the intracellular or extracellular Ca(2+) concentration. The GABA transporter inhibitors nipecotic acid and beta-alanine also had no effect. The ATP-stimulated [(3)H]GABA release was blocked, however, when media Cl(-) was replaced with gluconate and when extracellular HCO(3)(-) was removed. The Cl(-) channel/exchanger blockers 4,4'-diisothiocyanatostilbene-2',2'-disulfonic acid (DIDS) and 4-acetamido-4'- isothiocyanatostilbene-2',2'-disulfonic acids (SITS), but not diphenylamine-2-carboxylic acid (DPC) and furosemide, blocked the ATP-stimulated [(3)H]GABA release. The anionic selectivity of the process was F(-) > Cl(-) > Br(-) which is the same as that reported for volume-sensitive Cl(-) conductance. Treating cells with phorbol-12-myristate 13-acetate (PMA), forskolin, dibutyryl-cAMP, PD98059, neomycin, and D609 all inhibited the ATP-stimulated [(3)H]GABA release. We concluded that in RBA-2 cells, ATP stimulates [(3)H]GABA release through the P2X(7) receptors via a Cl(-)/HCO(3)(-)-dependent mechanism that is regulated by PKC, PKA, MEK/ERK, and PLD.
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Activation of P2X7 receptors induced [3H]GABA release from the RBA‐2 Type‐2 Astrocyte cell line through a Cl−/HCO3−‐dependent mechanism
Glia, 2001Co-Authors: Chiamei Wang, Yuanyi ChangAbstract:ATP is an important signaling molecule in the nervous system and it's signaling is mediated through the metabotropic P2Y and ionotropic P2X receptors. ATP is known to stimulate Ca2+ influx and phospholipase D (PLD) activity in the Type-2 Astrocyte cell line, RBA-2; in this study, we show that the release of preloaded [3H]GABA from RBA-2 cells is mediated through the P2X7 receptors. ATP and the ATP analogue 3′-O-(4-benoylbenoyl)-adenosine-5′-triphosphate (BzATP) both stimulated [3H]GABA release in a concentration dependent manner, while the nonselective P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), the P2X7-sensitive antagonist oxidized ATP (oATP), and high extracellular Mg2+ all inhibited the ATP-stimulated [3H]GABA release. The ATP-stimulated [3H]GABA release was not affected neither by removing extracellular Na+ nor by changes in the intracellular or extracellular Ca2+ concentration. The GABA transporter inhibitors nipecotic acid and β-alanine also had no effect. The ATP-stimulated [3H]GABA release was blocked, however, when media Cl− was replaced with gluconate and when extracellular HCO3− was removed. The Cl− channel/exchanger blockers 4,4′-diisothiocyanatostilbene-2′,2′-disulfonic acid (DIDS) and 4-acetamido-4′- isothiocyanatostilbene-2′,2′-disulfonic acids (SITS), but not diphenylamine-2-carboxylic acid (DPC) and furosemide, blocked the ATP-stimulated [3H]GABA release. The anionic selectivity of the process was F− > Cl− > Br− which is the same as that reported for volume-sensitive Cl− conductance. Treating cells with phorbol-12-myristate 13-acetate (PMA), forskolin, dibutyryl-cAMP, PD98059, neomycin, and D609 all inhibited the ATP-stimulated [3H]GABA release. We concluded that in RBA-2 cells, ATP stimulates [3H]GABA release through the P2X7 receptors via a Cl−/HCO3−-dependent mechanism that is regulated by PKC, PKA, MEK/ERK, and PLD. GLIA 37:8–18, 2002. © 2002 Wiley-Liss, Inc.
Amos C Hung - One of the best experts on this subject based on the ideXlab platform.
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roles of protein kinase c in regulation of p2x7 receptor mediated calcium signalling of cultured Type 2 Astrocyte cell line rba 2
Cellular Signalling, 2005Co-Authors: Amos C Hung, Juyun Weng, Hammer B Chen, Yinchung AuAbstract:Abstract The role of protein kinase C (PKC) on regulation of P2X 7 receptor-mediated Ca 2+ signalling was examined on RBA-2 Astrocytes. Activation of PKC decreased the receptor-mediated Ca 2+ signalling and the decrease was restored by PKC inhibitors. Down regulation of PKC also caused a decrease in the Ca 2+ signalling. Thus PKC might play a dual role on the P2X 7 receptor signalling. Successive stimulation of the P2X 7 receptor induced a gradual decline of Ca 2+ signalling but PKC inhibitors failed to restore the decline. Nevertheless, PMA stimulated translocation of PKC-α, -βI, -βII, and -γ, but only anti-PKC-γ co-immunoprecipitated the receptors. To examine the role of PKC-γ, Ca 2+ signalling was measured by Ca 2+ imaging. Our results revealed that the agonist-stimulated Ca 2+ signalling were reduced in the cells that the transfection of either P2X 7 receptor or PKC-γ morpholino antisense oligo was identified. Thus, we concluded that PKC-γ interacted with P2X 7 receptor complex and positively regulated the receptor-mediated Ca 2+ signalling.
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atp stimulated ca2 influx and phospholipase d activities of a rat brain derived Type 2 Astrocyte cell line rba 2 are mediated through p2x7 receptors
Journal of Neurochemistry, 2002Co-Authors: Amos C HungAbstract:This study characterizes and examines the P2 receptor-mediated signal transduction pathway of a rat brain-derived Type 2 Astrocyte cell line, RBA-2. ATP induced Ca 2+ influx and activated phospholipase D (PLD). The ATP-stimulated Ca 2+ influx was inhibited by pretreating cells with P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), in a concentration-dependent manner. The agonist 2'-and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) stimulated the largest increases in intracellular Ca 2+ concentrations ([Ca 2+ ] i ); ATP, 2-methylthioadenosine triphosphate tetrasodium, and ATPγS were much less effective, whereas UTP, ADP, α,β-methylene-ATP, and β,γ-methylene-ATP were ineffective. Furthermore, removal of extracellular Mg 2+ enhanced the ATP- and BzATP-stimulated increases in [Ca 2+ ] i . BzATP stimulated PLD in a concentration- and time-dependent manner that could be abolished by removal of extracellular Ca 2+ and was inhibited by suramin, PPADS, and oxidized ATP. In addition, PLD activities were activated by the Ca 2+ mobilization agent, ionomycin, in an extracellular Ca 2+ concentration-dependent manner. Both staurosporine and prolonged phorbol ester treatment inhibited BzATP-stimulated PLD activity. Taken together, these data indicate that activation of the P2X 7 receptors induces Ca 2+ influx and stimulates a Ca 2+ -dependent PLD in RBA-2 Astrocytes. Furthermore, protein kinase C regulates this PLD.
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the p2x7 receptor mediated phospholipase d activation is regulated by both pkc dependent and pkc independent pathways in a rat brain derived Type 2 Astrocyte cell line rba 2
Cellular Signalling, 2002Co-Authors: Amos C HungAbstract:Abstract The aim of this study was to characterize the regulatory mechanisms of the P2X7 receptor (P2X7R)-mediated phospholipase D (PLD) activation in a rat brain-derived Type-2 Astrocyte cell line, RBA-2. A time course study revealed that activation of P2X7R resulted in a choline and not phosphorylcholine formation, suggesting that activation of P2X7R is associated with the phosphatidylcholine–PLD (PC–PLD) in these cells. GF 109203X, a selective protein kinase C (PKC) inhibitor, partially inhibited the P2X7R-mediated PLD activation, while blocking the phorbol 12-myristate 13-acetate (PMA)-stimulated PLD activity. In addition, PMA synergistically activated the P2X7R-mediated PLD activity. Furthermore, genistein, a tyrosine kinase inhibitor, blocked the P2X7R-activated PLD, while KN62, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, was less effective, whereas the mitogen-activated protein kinase (MAPK) inhibitor PD98059 was ineffective. No additive inhibitory effects were found by simultaneous treatment of GF 109203X and KN62 on P2X7R-activated PLD. Taken together, these results demonstrate that both PKC-dependent and PKC-independent signaling pathways are involved in the regulation of P2X7R-mediated PLD activation. Additionally, CaMKII may participate in the PKC-dependent pathway, and tyrosine kinase may play a pivotal role on both PKC-dependent and PKC-independent pathways in the P2X7R-mediated PLD activation in RBA-2 cells.
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atp stimulated c fos and zif268 mrna expression is inhibited by chemical hypoxia in a rat brain derived Type 2 Astrocyte cell line rba 2
Journal of Cellular Biochemistry, 2000Co-Authors: Amos C Hung, Hsuehmeei Huang, Hueyjen TsayAbstract:The stimulus-transcriptional coupling during ischemia/hypoxia was examined for ATP-stimulated expression of immediate early genes (IEGs; c-fos, zif268, c-myc and nur77) in a rat brain-derived Type 2 Astrocyte cell line, RBA-2. Incubation of cells with 1 mM of extracellular ATP stimulated time-dependent expression of c-fos and zif268. ATP induced the largest increases in zif268 mRNA and a lesser one in c-fos mRNA. ATP also induced a slight increase in nur77 mRNA but was ineffective in inducing c-myc expression in these cells. Brief exposure of cells to potassium cyanide to simulate chemical hypoxia induced 9-fold and 7-fold transient increases in c-fos and zif268 expression, respectively, but did not affect c-myc or nur77 expression. When cyanide and ATP were added together, the expression of c-fos and zif268 expression was inhibited, and the effect was mimicked by simulating chemical hypoxia with sodium azide. To elucidate the mechanism involved, the effect of cyanide on ATP-stimulated increases in intracellular Ca2+ concentrations, [Ca2+]i, and phospholipase D (PLD) activities were measured. Cyanide induced an increase in [Ca2p]i and further enhanced the ATP-stimulated increases in [Ca2+]i and PLD activities. Nevertheless, metabolic inhibitor, iodoacetate, blocked the ATP-induced c-fos and partially inhibited zif268 expression, and deprivation of cells with glucose also inhibited the ATP-induced c-fos expression. Taken together, these results demonstrate that both extracellular ATP and chemical hypoxia induce c-fos and zif268 expression in RBA-2 Type 2 Astrocytes. The chemical hypoxia inhibited ATP-stimulated c-fos and zif268 expression is not due to alterations in Ca2+ and PLD signaling, and is at least partially related to metabolic disturbance in these cells. J. Cell. Biochem. 77:323–332, 2000. © 2000 Wiley-Liss, Inc.
Margot Mayerproschel - One of the best experts on this subject based on the ideXlab platform.
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oligodendrocyte Type 2 Astrocyte progenitor cells and glial restricted precursor cells generate different tumor phenoTypes in response to the identical oncogenes
The Journal of Neuroscience, 2013Co-Authors: Jun Wang, Margot Mayerproschel, Jared Bushman, Xi Wang, Mahlon D Johnson, Mark NobleAbstract:Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two Types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/Type-2 Astrocyte progenitor cells (O-2A/OPCs), and in Astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU. In vivo, cells differed in their ability to form tumors, in malignancy and even in the Type of host-derived cells infiltrating the tumor mass. Moreover, identical genetic modification of these different cells yielded benign infiltrative astrocytomas, malignant astrocytomas, or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas, indicating a contribution of cell-of-origin to the characteristic properties expressed by these different tumors. Our studies also revealed unexpected relationships between the cell-of-origin, differentiation, and the order of oncogene acquisition at different developmental stages in enabling neoplastic growth. These studies thus provide multiple novel demonstrations of the importance of the cell-of-origin in respect to the properties of transformed cells derived from them. In addition, the approaches used enable analysis of the role of cell-of-origin in tumor biology in ways that are not accessible by other more widely used approaches.
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the tripotential glial restricted precursor grp cell and glial development in the spinal cord generation of bipotential oligodendrocyte Type 2 Astrocyte progenitor cells and dorsal ventral differences in grp cell function
The Journal of Neuroscience, 2002Co-Authors: Ninel Z Gregori, Mark Noble, Christoph Proschel, Margot MayerproschelAbstract:We have found that the tripotential glial-restricted precursor (GRP) cell of the embryonic rat spinal cord can give rise in vitro to bipotential cells that express defining characteristics of oligodendrocyte-Type-2 Astrocyte progenitor cells (O2A/OPCs). Generation of O2A/OPCs is regulated by environmental signals and is promoted by platelet-derived growth factor (PDGF), thyroid hormone (TH) and Astrocyte-conditioned medium. In contrast to multiple observations indicating that oligodendrocyte precursor cells in the embryonic day 14 (E14) spinal cord are ventrally restricted, GRP cells are already present in both the dorsal and ventral spinal cord at E13.5. Ventral-derived GRP cells, however, were more likely to generate O2A/OPCs and/or oligodendrocytes than were their dorsal counterparts when exposed to TH, PDGF, or even bone morphogenetic protein-4. The simplest explanation of our results is that oligodendrocyte generation occurs as a result of generation of GRP cells from totipotent neuroepithelial stem cells, of O2A/OPCs from GRP cells and, finally, of oligodendrocytes from O2A/OPCs. In this respect, the responsiveness of GRP cells to modulators of this process may represent a central control point in the initiation of this critical developmental sequence. Our findings provide an integration between the earliest known glial precursors and the well-studied O2A/OPCs while opening up new questions concerning the intricate spatial and temporal regulation of precursor cell differentiation in the CNS.
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quantitative insight into proliferation and differentiation of oligodendrocyte Type 2 Astrocyte progenitor cells in vitro
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Andrej Y Yakovlev, Kenneth M Boucher, Margot Mayerproschel, Mark NobleAbstract:As part of our attempts at understanding fundamental principles that underlie the generation of nondividing terminally differentiated progeny from dividing precursor cells, we have developed approaches to a quantitative analysis of proliferation and differentiation of oligodendrocyte Type 2 Astrocyte (O-2A) progenitor cells at the clonal level. Owing to extensive previous studies of clonal differentiation in this lineage, O-2A progenitor cells represent an excellent system for such an analysis. Previous studies have resulted in two competing hypotheses; one of them suggests that progenitor cell differentiation is symmetric, the other hypothesis introduces an asymmetric process of differentiation. We propose a general model that incorporates both such extreme hypotheses as special cases. Our analysis of experimental data has shown, however, that neither of these extreme cases completely explains the observed kinetics of O-2A progenitor cell proliferation and oligodendrocyte generation in vitro. Instead, our results indicate that O-2A progenitor cells become competent for differentiation after they complete a certain number of critical mitotic cycles that represent a period of symmetric development. This number varies from clone to clone and may be thought of as a random variable; its probability distribution was estimated from experimental data. Those O-2A cells that have undergone the critical divisions then may differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability, thereby exhibiting the asymmetric Type of differentiation.
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on the track of cell survival pharmaceuticals in the oligodendrocyte Type 2 Astrocyte lineage
Perspectives on developmental neurobiology, 1996Co-Authors: Mark Noble, Margot MayerproschelAbstract:: The identification of compounds that can protect cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors is of great interest in contemporary biology. We have found that N-acetyl-L-cysteine (NAC) is able to promote cell survival in these two distinct experimental paradigms of, respectively, "death by murder" and "death by neglect." In the former case, NAC prevented the death of oligodendrocytes induced by glutamate or tumor necrosis factor-alpha (TNF-alpha), and also prevented TNF-alpha-induced death of L929 cells. NAC also acted in synergy with ciliary neurotrophic factor (CNTF) to prevent killing of oligodendrocytes by TNF-alpha. In analysis of "death by neglect," NAC markedly enhanced the extent of spinal ganglion neuron survival obtained with suboptimal concentrations of nerve growth factor and of oligodendrocyte survival obtained with suboptimal concentrations of CNTF or insulin-like growth factor-1. Surprisingly, significant rescue of oligodendrocytes from apoptosis was also observed with combinations of NAC with progesterone, vitamin C, or Trolox, a water-soluble vitamin E analogue, although not with any of these compounds applied individually. These results demonstrate that cocktails of small molecules such as those we have studied may have beneficial effects not predictable from the action of any individual member of the cocktail. In light of the long clinical history of therapeutic use of NAC and the other compounds identified in our studies, we suggest that it may be of interest to examine use of NAC alone, or combinations of NAC with the other small molecules we have studied, in conditions in which certain toxin-mediated forms of cell death or apoptosis contribute significantly to disease.
Martin Raff - One of the best experts on this subject based on the ideXlab platform.
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extracellular matrix associated molecules collaborate with ciliary neurotrophic factor to induce Type 2 Astrocyte development
Journal of Cell Biology, 1990Co-Authors: Laura E Lillien, Michael Sendtner, Martin RaffAbstract:O-2A progenitor cells give rise to both oligodendrocytes and Type-2 Astrocytes in vitro. Whereas oligodendrocyte differentiation occurs constitutively, Type-2 Astrocyte differentiation requires extracellular signals, one of which is thought to be ciliary neurotrophic factor (CNTF). CNTF, however, is insufficient by itself to induce the development of stable Type-2 Astrocytes. In this report we show the following: (a) that molecules associated with the extracellular matrix (ECM) cooperate with CNTF to induce stable Type-2 Astrocyte differentiation in serum-free cultures. The combination of CNTF and the ECM-associated molecules thus mimics the effect of FCS, which has been shown previously to induce stable Type-2 Astrocyte differentiation in vitro. (b) Both the ECM-associated molecules and CNTF act directly on O-2A progenitor cells and can induce them to differentiate prematurely into Type-2 Astrocytes. (c) ECM-associated molecules also inhibit oligodendrocyte differentiation, even in the absence of CNTF, but this inhibition is not sufficient on its own to induce Type-2 Astrocyte differentiation. (d) Whereas the effect of ECM on oligodendrocyte differentiation is mimicked by basic fibroblast growth factor (bFGF), the effect of ECM on Type-2 Astrocyte differentiation is not. (e) The ECM-associated molecules that are responsible for inhibiting oligodendrocyte differentiation and for cooperating with CNTF to induce Type-2 Astrocyte differentiation are made by non-glial cells in vitro. (f) Molecules that have these activities and bind to ECM are present in the optic nerve at the time Type-2 Astrocytes are thought to be developing.
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analysis of the cell cell interactions that control Type 2 Astrocyte development in vitro
Neuron, 1990Co-Authors: Laura E Lillien, Martin RaffAbstract:Abstract Oligodendrocytes and Type-2 Astrocytes develop sequentially from O-2A progenitor cells in the rat CNS. We have reproduced this sequential development in a simplified, serum-free in vitro system: in cultures of newborn optic nerve cells treated with platelet-derived growth factor to maintain O-2A progenitor cell proliferation, progenitor cells differentiate into oligodendrocytes during the first week in vitro and into Type-2 Astrocytes during the second week. Thus all of the signals needed for Type-2 Astrocyte development are made by serum-free optic nerve cultures, indicating that neurons are not required. By manipulating the cellular composition of the cultures, we provide evidence that Type-2 Astrocyte development does not depend on oligodendrocytes, but instead requires non-0-2A lineage cells, which are also responsible for timing this development.
