The role of GSK3-beta pathway in oligodendroglial progenitor cell differentiation and remyelination after spinal cordi Injury

Abstract

Background: Demyelination is one of the major obstacle for axon regeneration and functional recovery after SCI. Previous research has shown that a pool of resident neural progenitor cells (NPCs) in spinal cord can be recruited to produce progeny after injury. Our preliminary study shows that lithium and noggin stimulate oligodendrocyte differentiation of adult spinal cord-derived NPC (ASCNPC) and lithium exerts its effect by inhibiting GSK3β pathway. Objectives: To examine whether GSK3β inhibition leads to oligodendroglial progenitor cell differentiation and remyelination, and functional recovery after SCI. Methods: Adult mice were subjected to contusive injury at 8th-10th thoracic level. Twenty-four hours after injury, spinal cord segments were harvested for neurosphere culture. Neurosphere cells were treated with GSK3β inhibitors ARA-014418 and lithium and cultured in differentiating medium. Two weeks after SCI, mice were treated with ARA-014418 and lithium for two weeks before the 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 GSK3β inhibitors exhibit better performance in BMS. The myelinated area and volume of treated spinal cords were partially rescued by GSK3β inhibitor treatment. Conclusions: Both GSK3β inhibitors ARA-014418 and lithium are effective in promoting oligodendrocyte/neuron differentiation and functional recovery after SCI. It indicates that GSK3β is a key player in impeding SCI repair