title: Change of fate commitment in adult neural progenitor cells subjected to chronic inflammation.
abstract: Neural progenitor cells (NPCs) have regenerative capabilities that are activated during inflammation. We aimed at elucidating how NPCs, with special focus on the spinal cord-derived NPCs (SC-NPCs), are affected by chronic inflammation modeled by experimental autoimmune encephalomyelitis (EAE). NPCs derived from the subventricular zone (SVZ-NPCs) were also included in the study as a reference from a distant inflammatory site. We also investigated the transcriptional and functional difference between the SC-NPCs and SVZ-NPCs during homeostatic conditions. NPCs were isolated and propagated from the SVZ and cervical, thoracic, and caudal regions of the SC from naive rats and rats subjected to EAE. Using Affymetrix microarray analyses, the global transcriptome was measured in the different NPC populations. These analyses were paralleled by NPC differentiation studies. Assessment of basal transcriptional and functional differences between NPC populations in naive rat revealed a higher neurogenic potential in SVZ-NPCs compared with SC-NPCs. Conversely, during EAE, the neurogenicity of the SC-NPCs was increased while their gliogenicity was decreased. We detected an overall increase of inflammation and neurodegeneration-related genes while the developmentally related profile was decreased. Among the decreased functions, we isolated a gliogenic signature that was confirmed by differentiation assays where the SC-NPCs from EAE generated fewer oligodendrocytes and astrocytes but more neurons than control cultures. In summary, NPCs displayed differences in fate-regulating genes and differentiation potential depending on their rostrocaudal origin. Inflammatory conditions downregulated gliogenicity in SC-NPCs, promoting neurogenicity. These findings give important insight into neuroinflammatory diseases and the mechanisms influencing NPC plasticity during these conditions.
authors.affiliation: Division of Neurology, Center for Molecular Medicine.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Covacu
authors.affiliation: Division of Neurology, Center for Molecular Medicine.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Perez Estrada
authors.affiliation: Division of Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Arvidsson
authors.affiliation: Division of Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Svensson
authors.affiliation: Division of Neurology, Center for Molecular Medicine, lou.brundin@karolinska.se.
authors.forename: Lou
authors.initials: L
authors.lastname: Brundin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications*; D058953:Neural Stem Cells / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000166:cytology*; D059467:Transcriptome
keywords: differentiation; experimental autoimmune encephalomyelitis; gliogenesis; microarray; neural stem cells; neurogenesis