The Inhibition Of GSK3β Promotes Oligodendroglial Progenitor Cell Differentiation In Spinal Cord Injury

Abstract

Aims: Demyelination is one of the major obstacles for axon regeneration and functional recovery after spinal cord injury (SCI). Previous studies have shown that resident neural progenitor cells in spinal cord can be recruited to produce progenies after injury. Our preliminary study shows that lithium and noggin stimulate oligodendrocyte differentiation of adult spinal cord-derived neural stem/progenitor cells (ASCNPCs). Lithium may exert its effect by inhibiting GSK3ß pathway. Our study aims to examine whether GSK3ß inhibition leads to endogenous oligodendroglial progenitor cell differentiation and remyelination, and results in functional recovery after SCI.

Methods: Adult mice were subjected to spinal cord contusion at 8th-10th thoracic level. For neurosphere culture, injured spinal cords were harvested one day post injury (1 d.p.i.). The second passage neurosphere cells were treated with GSK3ß inhibitors ARA-014418 and lithium for seven days in differentiating medium. For in vivo experiments, injured mice were treated with lithium 21 d.p.i. for 14 days, before being sacrificed for myelin measurement. Basso Mouse Scale (BMS) was performed weekly after injury to monitor locomotion function.

Results: ARA-014418 and lithium promote both oligodendroglial and neuronal differentiation of ASCNPCs. Injured mice treated with GSK3ß inhibitors exhibit better performance in BMS. GSK3ß inhibitor also significantly decreased the area and volume of demyelination in the dorsal column of contused spinal cord.

Conclusions: Both GSK3ß inhibitors ARA-014418 and lithium are effective in promoting oligodendrocyte/neuron differentiation. Injured mice treated with GSK3ß inhibitors demonstrate better functional recovery. Our results indicate that GSK3ß may be a key player in impeding SCI repair.