Vitamin D3 promotes locomotor recovery by enhancing myelin integrity after experimental traumatic spinal cord injuries

Abstract

Traumatic spinal cord injury (TSCI) is a catastrophic neurological event that often leads to motor and sensory deficits. It not only disturbs the physical functions but also impairs the mental and social well-being. The incidence of TSCI is increasing due to society ageing, industrial development and vehicle popularization; however, the managements for TSCI remains limited. With the expansion in the understandings of post-traumatic physiopathology, more researches are being initiated to look for new therapies.

Demyelination resulting from oligodendrocytes (OLs) loss occurs after TSCI. Insufficient myelin regeneration or remyelination contributes to worse neural restoration; promoting remyelination and/or ameliorating myelin damage can benefit the functional recovery as reported by several studies. Vitamin D3 (VitD) is suggested as an effective regulator in cell proliferation and differentiation. It is already known that it drives OLs’ generation from neural stem cells and oligodendrocyte precursor cells (OPCs), indicating its potentials in treating demyelinating diseases. Indeed, VitD showed its myelin-regenerating benefits in multiple sclerosis and peripheral nerve injury model.

In the present study, demyelination was observed at the epicenters after TSCI, and the severities were in accordance with the completeness of injury. Myelin damage was also observed in the adjacent segments, especially in the rostral end. VitD treatment enhanced the integrity of myelin and promoted locomotor recovery. More interestingly, when further looking into the impacts of pre-existing VitD depletion on post-traumatic recovery, VitD-sufficient animals were likely to respond well to the treatment after complete transection in comparison with their Vit-Deficient counterparts.

In vitro data supported the notion that this benefit might be because of either a decrease in OLs apoptosis and/or an increase in OPCs differentiation. Further investigation demonstrated that VitD enhanced OPCs differentiation and functional maturation, as it increased the myelin basic protein level and promoted myelin formation surrounding dorsal root ganglia neurites in the co-culture system. At the meantime, VitD effectively suppressed the proliferation of OPCs. This observation indicated that there could be a determinator that modulated the balance between cell proliferation and differentiation under the regulation of VitD. Indeed, mTOR-c-Myc signalling was found to be inhibited upon VitD administration; knocking down c-Myc prohibited OPCs proliferation and enhanced their differentiation.

This study for the first time provides the evidence on the myelin-promoting role of VitD after TSCI. It also reveals a negative impact of pre-VitD deficiency on post-TSCI recovery, emphasizing the necessity of monitoring VitD status in routine health examination. It further illustrates a role of c-Myc as a dominant controller between VitD-induced proliferation suppression and differentiation enforcement, thus uncovering another of c-Myc’s biological functions apart from its pro-tumorigenesis properties. These data shed lights on VitD’s value in TSCI treatment. Further studies into the mechanisms of VitD signalling in myelin regeneration are encouraged.