title: STAT3 represents a molecular switch possibly inducing astroglial instead of oligodendroglial differentiation of oligodendroglial progenitor cells in Theiler's murine encephalomyelitis.
abstract: OBJECTIVE
  Insufficient oligodendroglial differentiation of oligodendroglial progenitor cells (OPCs) is suggested to be responsible for remyelination failure and astroglial scar formation in Theiler's murine encephalomyelitis (TME). The aim of the present study is to identify molecular key regulators of OPC differentiation in TME, and to dissect their mechanism of action in vitro.
  
  
  METHODS
  TME virus (TMEV) infected SJL/J-mice were evaluated by rotarod analysis, histopathology, immunohistology and gene expression microarray analysis. The STAT3 pathway was activated using meteorin and inhibited using STAT3 inhibitor VII in the glial progenitor cell line BO-1 and in primary rat OPCs in vitro.
  
  
  RESULTS
  As expected, immunohistology demonstrated progressively decreasing myelin basic protein-positive white matter in TME. In contrast, intralesional NG2-positive OPCs as well as GFAP-positive astrocytes were increased. Gene Set Enrichment Analysis revealed 26 Gene Ontology terms including 'JAK-STAT cascade' to be significantly positively correlated with the density of NG2-positive OPCs. Immunohistology revealed an increased amount of activated, phosphorylated STAT3-expressing astrocytes, OPCs, and microglia/macrophages within the lesions. Meteorin-induced activation of STAT3-signalling in BO-1 cells and primary rat OPCs resulted in an enhanced GFAP and reduced CNPase expression. In contrast, an oppositional result was observed in BO-1 cells treated with STAT3 inhibitor VII.
  
  
  CONCLUSIONS
  The STAT3 pathway is a key regulator of OPC-differentiation, suggested to shift their differentiation from an oligodendroglial towards an astrocytic fate, thereby inducing astrogliosis and insufficient remyelination in TME.
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany; Centre for Systems Neuroscience Hannover, Hannover, Germany.
authors.forename: Yanyong
authors.initials: Y
authors.lastname: Sun
authors.forename: Annika
authors.initials: A
authors.lastname: Lehmbecker
authors.forename: Arno
authors.initials: A
authors.lastname: Kalkuhl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Deschl
authors.forename: Wenhui
authors.initials: W
authors.lastname: Sun
authors.forename: Karl
authors.initials: K
authors.lastname: Rohn
authors.forename: Iva D
authors.initials: ID
authors.lastname: Tzvetanova
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D018188:Cardiovirus Infections / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017945:Theilovirus
chemical_list: D050796:STAT3 Transcription Factor
keywords: Janus kinase; Theiler's murine encephalomyelitis; microarray; multiple sclerosis; oligodendrocyte progenitor cell; signal transducer and activator of transcription