Migration of olfactory ensheathing cells grafted into adult rat spinal cord

Olfactory ensheathing cells (OECs) are non-myelinating glial cells that provide ensheathment for axons of the olfactory nerve in vivo. OECs have been shown to facilitate the regeneration of CNS axons, to assemble a myelin sheath around demyelinated axons, and it has been suggested OECs migrate very well within the microenvironment of the injured CNS. However, there has been no direct test of their migratory ability in vivo. The aims of this study were to determine whether: 1) OECs can be induced to migrate towards an ethidium bromide (EtBr)-induced focal (~1 mm long) demyelination of the spinal cord white matter; 2) OECs migrate away from a focal demyelination either into normal CNS tissue or towards a second demyelinated lesion; 3) microglial reactivity is required for the generation of the migratory signal(s) inducing OECs to migrate towards a focal demyelination; 4) OECs grafted into the subarachnoid space surrounding the spinal cord will migrate into the neuropil in the absence of demyelination. To achieve these aims, we developed an in vivo model for studying the migratory ability of OECs within the adult rat spinal cord. A small focal EtBr-induced demyelination of the dorsal funiculus (unilaterally) of the spinal cord was made at variable distances from the site of a DiI-labelled OEC graft. The major findings were: i) the strength of the migratory signal(s) inducing OECs to migrate increased as the demyelinated lesion was located closer to the grafting site; ii) the OEC migration towards a distal demyelinated lesion was greatly enhanced when the cells were grafted directly into a second demyelinated lesion; iii) the cell migration occurred along a migratory path containing many reactive astrocytes and microglia; iv) the migration of OECs was significantly reduced when the microglial reactivity was dampened using minocycline; and v) OECs survived grafting into cerebrospinal fluid (i.e. subarachnoid space) and migrated into the neuropil of the brain and spinal cord. The major conclusions are that OECs can respond to migratory signal(s) arising as a result of a focal EtBr-induced demyelination and that microglia are one potential source of these migratory signal(s)

The Double-Edged Sword of Autoimmunity: Lessons from Multiple Sclerosis

The relationship between immune responses to self-antigens and autoimmune disease is unclear. In contrast to its animal model experimental autoimmune encephalomyelitis (EAE), which is driven by T cell responses to myelin antigens, the target antigen of the intrathecal immune response in multiple sclerosis (MS) has not been identified. Although the immune response in MS contributes significantly to tissue destruction, the action of immunocompetent cells within the central nervous system (CNS) may also hold therapeutic potential. Thus, treatment of MS patients with glatiramer acetate triggers a protective immune response. Here we review the immunopathogenesis of MS and some recent findings on the mechanism of glatiramer acetate (GA)

LacZ-expressing olfactory ensheathing cells do not associate with myelinated axons after implantation into the compressed spinal cord

Studies have shown that implanting olfactory ensheathing cells (OECs) may be a promising therapeutic strategy to promote functional recovery after spinal cord injury. Several fundamental questions remain, however, regarding their in vivo interactions in the damaged spinal cord. We have induced a clip compression injury at the T10 level of the spinal cord in adult rats. After a delay of 1 week, OECs isolated from embryonic day 18 rats were implanted into the cystic cavity that had formed at the site of injury. Before implantation, OECs were infected with a LacZ-expressing retrovirus. At 3 weeks after implantation, LacZ-expressing OECs survived the implantation procedure and remained localized to the cystic cavity. At the electron microscopic level, the cystic cavity had clusters of LacZ-expressing OECs and numerous Schwann cells lacking LacZ expression. Although labeled OECs made no direct contact with axons, unlabeled Schwann cells were associated with either a single myelinated axon or multiple unmyelinated axons. Positively labeled OEC processes often enveloped multiple Schwann cell-axon units. These observations suggest that the role of OECs as the primary mediators of the beneficial effects on axon growth, myelination, and functional recovery after spinal cord injury may require re-evaluation

Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate

The formation of oligodendrocytes (oligodendrogenesis) and myelin is regulated by several neurotrophic factors. Strategies to increase the level of these trophic molecules may facilitate repair in demyelinating conditions, such as multiple sclerosis (MS). Because leukocytes are a source of neurotrophic factors, and as glatiramer acetate (GA) generates T helper 2 (Th2) lymphocytes that are not known to be harmful, we tested the hypothesis that GA regulates oligodendrogenesis and myelin formation. First, we generated GA-reactive Th2 cells and determined that they produced transcripts for neurotrophic factors, including insulin-like growth factor-1 (IGF-1). The conditioned medium from GA-reactive T cells elevated IGF-1 protein and promoted the formation of oligodendrocyte precursor cells (OPCs) from embryonic brainderived forebrain cells in culture. We next subjected mice to lysolecithin-induced demyelination of the spinal cord. At 7 days after the insult, the number of OPCs in the demyelinated dorsal column was higher than that in uninjured controls, and was further increased by the daily s.c. injection with GA. Increased OPC generation by GA was associated temporally with the elevation of IGF-1 and brain-derived neurotrophic factor (BDNF) in the spinal cord. Finally, the resultant remyelination at 28 days was higher in mice treated with GA during the first 7 days of injury compared with vehicle controls. These results indicate that GA promotes oligodendrogenesis and remyelination through mechanisms that involve the elevation of growth factors conducive for repair