Myelin-forming cells enwrap axons to allow fast conduction along major nerve tracts. In multiple sclerosis (MS) and some CNS viral diseases, damage to myelin-forming cells result in important neurological dysfunction. Our studies of the human oligodendrocyte lineage demonstrate that the human myelinated brain contains a discrete subpopulation of glial cells expressing two oligodendrocyte-specific and developmentally regulated genes, the PDGF receptor alpha and the myelin transcription factor 1 (MTF1). Precursors of oligodendrocytes are also identified in cultures of adult human white matter. bFGF induces human oligodendrocytes to rapidly regenerate their processes and to dedifferentiate without going through mitosis. This suggests that phenotypic plasticity rather than mitogenic potential may account for the regeneration of myelin-forming cells in the adult human brain. We are therefore working toward the establishment of a human oligodendrocyte cell line by transferring growth factor receptor genes with the hope of obtaining oligodendrocyte mitosis in response to known growth factors. An oligodendrocyte growth factor dependent cell line has indeed been successfully established in the rat and shown to be able to myelinate myelin-deficient rats after grafting in the spinal cord. Moreover, such cells, transfected with a marker gene, were shown to migrate up to 12 mm along the dorsal column and integrate well into the white matter. Thus, rat oligodendrocytes progenitors can maintain their ability to migrate and myelinate in vivo after multiple passages. This suggest that such cell lines might be useful to correct genetic defects of myelination in mice and men. Another focus of our research is on the mechanisms of remyelination and recurrent demyelination in rodent and men. During remyelination, there is an increase in myelin basic protein (MBP) transcripts that are characteristic of the premyelinating stage. Importantly, an immune response to specific peptide sequences encoded by these transcripts have been correlated with disease activity in familial forms of MS. We are therefore examining in two different animal models whether the reemergence of these MBP isoforms triggers a T lymphocyte response specific for these proteins and can be correlated with disease perpetuation.
