STAT3 represents a molecular switch possibly inducing astroglial instead of oligodendroglial differentiation of oligodendroglial progenitor cells in Theiler's murine encephalomyelitis

Authors

  • Yanyong Sun,

    1. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
    2. Centre for Systems Neuroscience Hannover, Hannover, Germany
    Search for more papers by this author
  • Annika Lehmbecker,

    1. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
    2. Centre for Systems Neuroscience Hannover, Hannover, Germany
    Search for more papers by this author
  • Arno Kalkuhl,

    1. Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma, Biberach (Riß), Germany
    Search for more papers by this author
  • Ulrich Deschl,

    1. Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma, Biberach (Riß), Germany
    Search for more papers by this author
  • Wenhui Sun,

    1. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
    2. Centre for Systems Neuroscience Hannover, Hannover, Germany
    Search for more papers by this author
  • Karl Rohn,

    1. Department of Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, Hannover, Germany
    Search for more papers by this author
  • Iva D. Tzvetanova,

    1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Search for more papers by this author
  • Klaus-Armin Nave,

    1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Search for more papers by this author
  • Wolfgang Baumgärtner,

    1. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
    2. Centre for Systems Neuroscience Hannover, Hannover, Germany
    Search for more papers by this author
  • Reiner Ulrich

    Corresponding author
    1. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany
    2. Centre for Systems Neuroscience Hannover, Hannover, Germany
    • Correspondence: Reiner Ulrich, Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany. Tel: +495 11 953 8670; Fax: +49 511 953 8675; E-mail: Reiner.Ulrich@tiho-hannover.de

    Search for more papers by this author

Abstract

Aims

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.

Ancillary