Functional Recovery in Traumatic Spinal Cord Injury after Transplantation of Multineurotrophin-Expressing Glial-Restricted Precursor Cells

Abstract

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).UltrastructuralanalysisshowedthatthegraftedGRPsformedmorphologicallynormal-appearingmyelinsheathsaroundtheaxonsinthe ventrolateral funiculus (VLF) of spinal cord. Expression of D15A significantly increased the percentage of APC ϩ 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.

Loss and spontaneous recovery of forelimb evoked potentials in both the adult rat cuneate nucleus and somatosensory cortex following contusive cervical spinal cord injury

“…Their latencies significantly improved with time post-transplantation. Similar to the present findings, however, the latencies were slower than normal even at 3 weeks after the SCI (Cao et al, 2005).…”

“…This suggestion is supported by the report that a progressive oligodendrocyte and Schwann cell remyelination began in the adult rat spinal cord white matter during the first week following maximal demyelination at day 1 after contusive thoracic SCI (Totoiu and Keirstead, 2005). Additional support of this suggestion is the finding (Cao et al, 2005) that transcranial magnetic motor evoked potentials (Linden et al, 1999;Loy et al, 2002) that were abolished following contusive thoracic SCI recovered 1 week after transplantation of multineurotrophin-expressing glial-restricted precursor cells into the adult rat spinal cord ventrolateral funiculus (Cao et al, 2005). Their latencies significantly improved with time post-transplantation.…”

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

“…Still, the degree to which GRPs form myelinating oligodendrocytes in the contused spinal cord is somewhat limited . Furthermore, it appears that behavioral recovery requires the transduction with the neurotrophin D15A (Cao et al, 2005), which has BDNF and NT-3 activities and also enhances oligodendrocyte differentiation. The extent to which the observed benefits are related to increased myelination, neuroprotection, or neural plasticity can only be speculated on.…”

Oligodendrocyte Fate after Spinal Cord Injury

“…The authors also suggested a prior need to differentiate the cells in vitro into restricted lineages before transplantation. The same group demonstrated that transplantation of embryonic glial restricted precursor cells over-expressing BDNF and NT-3 at 9 days after injury resulted in increased OL formation (15-30%), enhanced remyelination, and restored electrophysiological conduction resulting in improved locomotor function [165].…”