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STAT 3 represents a molecular switch possibly inducing astroglial instead of oligodendroglial differentiation of oligodendroglial progenitor cells in Theiler's murine encephalomyelitis
Author(s) -
Sun Yanyong,
Lehmbecker Annika,
Kalkuhl Arno,
Deschl Ulrich,
Sun Wenhui,
Rohn Karl,
Tzvetanova Iva D.,
Nave KlausArmin,
Baumgärtner Wolfgang,
Ulrich Reiner
Publication year - 2015
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12133
Subject(s) - remyelination , astrogliosis , biology , progenitor cell , microglia , microbiology and biotechnology , stat , stat3 , oligodendrocyte , cellular differentiation , immunology , myelin , stem cell , signal transduction , neuroscience , gene , central nervous system , genetics , inflammation
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 STAT 3 pathway was activated using meteorin and inhibited using STAT 3 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. G ene S et E nrichment A nalysis revealed 26 G ene O ntology 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 STAT 3 inhibitor VII . Conclusions The STAT 3 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 .