title: The Neurogenic Potential of Astrocytes Is Regulated by Inflammatory Signals.
abstract: Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these 'reactive' astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes.
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.|Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, Avenue des Hauts-Fourneaux, L-4362, Esch-Belval, Luxembourg.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Michelucci
authors.affiliation: School of Pharmacy, Department of Pharmacology, The Hopkins Building, University of Reading, Whiteknights, Reading, RG6 6AP, UK. a.bithell@reading.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Bithell
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burney
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Johnston
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore, 138672, Singapore.
authors.forename: Kee-Yew
authors.initials: KY
authors.lastname: Wong
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore, 138672, Singapore.
authors.forename: Siaw-Wei
authors.initials: SW
authors.lastname: Teng
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Jyaysi
authors.initials: J
authors.lastname: Desai
authors.affiliation: School of Pharmacy, Department of Pharmacology, The Hopkins Building, University of Reading, Whiteknights, Reading, RG6 6AP, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Gumbleton
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Gregory
authors.initials: G
authors.lastname: Anderson
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore, 138672, Singapore.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.affiliation: Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Brenda P
authors.initials: BP
authors.lastname: Williams
authors.affiliation: Department of Psychiatry, Warneford Hospital, University of Oxford, Warneford Lane, Oxford, OX3 7JX, UK. noel.buckley@psych.ox.ac.uk.
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D055415:Bone Morphogenetic Protein 4; D006657:Histones; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha
keywords: Astrocytes; Epigenetic; Inflammation; NFκB; Neural stem cells; Noggin