Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions

Abstract

Many oligodendrocyte progenitor cells (OPCs) are found in acute or chronic demyelinated area, but not all of them differentiate efficiently into mature oligodendrocytes in the demyelinated central nervous system (CNS). Recent studies have shown that the basic helix-loop-helix transcription factor Olig2, which stimulates OPCs to differentiate into oligodendrocyte, is strongly up-regulated in many pathological conditions including acute or chronic demyelinating lesions in the adult CNS. Despite their potential role in the treatment of demyelinating diseases, the long-term fate of these up-regulated Olig2 cells has not been identified due to the lack of stable labeling methods. To trace their fate we have used double-transgenic mice, in which we were able to label Olig2-positive cells conditionally with green fluorescent protein (GFP). Demyelination was induced in these mice by feeding cuprizone, a copper chelator. After 6 weeks of cuprizone exposure, GFP-positive (GFP +) cells were processed for a second labeling with antibodies to major neural cell markers APC (mature oligodendrocyte marker), GFAP (astrocyte marker), NeuN (neuron marker), Iba1 (microglia marker) and NG2 proteoglycan (oligodendrocyte progenitor marker). More than half of the GFP + cells in the external capsule showed co-localization with NG2 proteoglycan. While the percentages of NG2-positive (NG2 +) and APC-positive (APC +) oligodendrocyte lineage cells in cuprizone-treated mice were significantly higher than those in the normal diet group, no significant difference was observed for GFAP-positive (GFAP +) astrocytic lineage cells. Our data therefore provide direct evidence that proliferation and differentiation of local and/or recruited Olig2 progenitors contribute to remyelination in demyelinated lesions.