Schwann cells and their precursors for repair of central nervous system myelin.

In multiple sclerosis (MS), axons of the central nervous system lose their myelin sheaths, and there is also death of oligodendrocytes. Although some demyelinated axons rebuild their membranes so that they can conduct action potentials in the absence of myelin insulation, others do not; and loss of the myelin thus impairs impulse conduction either temporarily or permanently. Mounting evidence also suggests that loss of central myelin may have the secondary consequence of making axons more sensitive to damage or may, in itself, produce changes that impair axonal integrity, thereby leading to cumulative loss of axons that culminates in irreversible neurological deficits (Waxman, 2006). While a number of treatments such as the beta interferons (IFN-b) and glatirimer acetate (GA) are now available for the treatment of MS, and clinical studies using autologous haematopoietic stem cell transplantation (HSCT) and monoclonal antibody interventions in MS patients have shown profound suppression of inflammatory activity in many patients, these interventions were developed in the attempt to mute the immune attack on the nervous system in MS, and not with the goal of repairing demyelination. Thus, even if the immune assault on the nervous system in MS could be halted by a new immunomodulatory therapy and the subsequent cascade of tissue damage thereby stalled, hundreds of thousands of people harboring MS lesions would still be left with neurological deficits. It is therefore not surprising that myelin repair has become an area of major interest in MS research. Important progress in this respect has come from studies that have examined cell-based approaches to myelin repair. A critical issue for cell-based myelin repair is the choice of cell type for transplantation. The transplanted cell must be able to survive, migrate to demyelinated lesions, remyelinate axons and not be tumorogenic. Oligodendrocyte lineage cells, neural progenitor cells, post-natal Schwann cells, olfactory ensheathing cells and other cell types have been shown to be able to migrate and remyelinate demyelinated CNS after transplantation directly into experimentally demyelinated lesions (Radtke et al., 2007). Importantly, appropriate ion channel organization at nodal and paranodal axon regions is reestablished in central axons remyelinated by endogenous or transplanted cells, and impulse conduction is improved (Black et al., 2006; Sasaki et al., 2006; Eftekharpour et al., 2007). However, as pointed out by Woodhoo et al. in this issue of Brain, the scattered nature of MS lesions and the inability of transplanted cells to migrate through normal white matter currently limit the therapeutic potential of cell transplantation for MS. While transplanted myelin-forming cells in general demonstrate an ability to remyelinate and display some degree of migration within demyelinated or traumatic CNS injury lesions, poor survival and migration within normal white matter (which may be present between lesions in MS) may limit their repair capacity (Franklin and Blakemore, 1997). One approach to this challenge is suggested by the observation that, while oligodendrocyte precursor cells (OPCs) survive poorly and do not migrate in normal CNS white matter, focal X-irradiation of the spinal cord results in development of an environment permissive for extensive OPC migration (Franklin and Blakemore, 1997). However, the level of radiation required to enhance OPC migration is high and can itself lead to post-radiation necrosis or myelopathy several months later, thus rendering X-irradiation as an adjunct to cell therapy for MS impractical. Transplanted Schwann cells derived from mature rats (Honmou et al., 1996) and from adult human nerves (Kohama et al., 2001) can remyelinate CNS axons and have been shown to improve conduction in demyelinated spinal cord lesions in the rat. There are substantial differences in the molecular makeup of oligodendrocyte and Schwann cell myelin. These differences may turn out to be clinically important since Schwann cell myelin is not affected in MS, and myelin formed by Schwann cells after transplantation to the CNS may not be a target for the destructive process in MS. However, the inability of post-natal Schwann cells to migrate extensively through normal white matter, or through astrocyte-rich environments such as glial scars, poses a serious limitation for the potential use of these cells for myelin repair in MS. Woodhoo and colleagues (2007) present interesting data showing that Schwann cell precursors (SCPs) derived from embryonic day 14 (E14) rat nerves survive transplantation into normal CNS, migrate through normal white matter, integrate with host glia, and are capable of remyelinating axons even when the SCPs are transplanted at some distance from the focal demyelinating lesion. The myelin formed by the SCPs is a peripheral type, containing the peripheral myelin protein P0. Thus, the Woodhoo et al. (2007) study suggests that SCPs may overcome the doi:10.1093/brain/awm161 Brain (2007), 130, 1978^1980