Remyelination strategies following spinal cord injury

Spinal cord injury (SCI) results in substantial oligodendrocyte death and demyelination. Remyelination is deemed critical because denuded axons not only lack the myelin necessary to achieve normal conduction velocity, but are also at increased risk of degeneration. A more rapid remyelination thus hypothesized to spare more axons from axonal degeneration, ultimately sparing neurological circuitry from the secondary damage that continues in the days and weeks following SCI. In this thesis I undertake two strategies to improve remyelination after SCI. In Chapter 2, I investigated whether transplantation of murine Platelet derived growth factor (PDGF)-responsive neural precursor cells (PRPs) could differentiate into remyelinating oligodendrocytes and improve functional recovery after SCI. Transplanted PRPs integrated into host tissue, differentiated into extensively branched mature oligodendrocytes that ensheathed multiple axons, and produced mature myelin. Thus, PRP-derived oligodendrocytes were capable of generating mature myelin sheaths on denuded CNS axons. To our surprise, although transplanted PRPs efficiently produced oligodendrocytes in the injured spinal cord, there was no significant increase in the total number of myelinated axons in PRP-transplanted versus media control animals. Likewise there was no improvement in behavioural recovery following transplantation in two separate experiments. Blocking known inhibitors of oligodendrocyte differentiation or maturation could improve remyelination. Myelin debris is present following SCI and inhibits oligodendrocyte development in vitro, and I hypothesized that myelin debris inhibits remyelination after SCI. In Chapter 3, oligodendrocyte precursor cells (OPCs) were grown in culture in the presence of myelin. Using this approach, I found that on myelin there was a robust inhibition of oligodendroglia maturation, without a corresponding increase in cell death or proliferation. To understand how myelin inhibits maturation, I measured the expression of a number of genes encoding well-characterized transcription factors that negatively regulate oligodendrocyte development. Associated with stalled maturation, I found myelin increases Inhibitor of Differentiation (ID) 2 and 4, which upon overexpression in OPCs is known to stall maturation. Thus, enhanced levels of ID2 and ID4 in oligodendroglia that are in contact with myelin provides a mechanistic understanding as to how myelin inhibits oligodendroglial maturation.Medicine, Faculty ofGraduat