Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells

Demyelination contributes to the physiological and behavioral deficits after contusive spinal cord injury ( SCI). Therefore, remyelination may be an important strategy to facilitate repair after SCI. We show here that rat embryonic day 14 spinal cord- derived glial- restricted precursor cells ( GRPs), which differentiate into both oligodendrocytes and astrocytes, formed normal- appearing central myelin around axons of cultured DRG neurons and had enhanced proliferation and survival in the presence of neurotrophin 3 ( NT3) and brain- derived neurotrophin factor ( BDNF). We infected GRPs with retroviruses expressing the multineurotrophin D15A ( with both BDNF and NT3 activities) and then transplanted them into the contused adult thoracic spinal cord at 9 d after injury. Expression of D15A in the injured spinal cord is five times higher in animals receiving D15A - GRP grafts than ones receiving enhanced green fluorescent protein ( EGFP) - GRP or DMEM grafts. Six weeks after transplantation, the grafted GRPs differentiated into mature oligodendrocytes expressing both myelin basic protein ( MBP) and adenomatus polyposis coli ( APC). Ultrastructural analysis showed that the grafted GRPs formed morphologically normal- appearing myelin sheaths around the axons in the ventrolateral funiculus ( VLF) of spinal cord. Expression of D15A significantly increased the percentage of APC (+) oligodendrocytes of grafted GRPs ( 15 - 30%). Most importantly, 8 of 12 rats receiving grafts of D15A - GRPs recovered transcranial magnetic motor- evoked potential responses, indicating that conduction through the demyelinated VLF axons was restored. Such electrophysiological recovery was not observed in rats receiving grafts of EGFP - GRPs, D15A - NIH3T3 cells, or an injection of an adenovirus expressing D15A. Recovery of hindlimb locomotor function was also significantly enhanced only in the D15A - GRP- grafted animals at 4 and 5 weeks after transplantation. Therefore, combined treatment with neurotrophins and GRP grafts can facilitate functional recovery after traumatic SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord.