Myelin-forming cells assume an essential function in the nervous system, allowing fast conduction to occur along major nerve tracks. Loss or alteration of myelin forming cells results in neurological dysfunction such as seen in multiple sclerosis (MS). The goals of this project are to study how the development of oligodendrocytes is controlled by several polypeptide growth factors made by neurons and astrocytes in the CNS. Platelet-derived growth factor (PDGF) controls the shape, motility, mitosis and timely differentiation of oligodendrocytes progenitors in a paracrine signalling loop which is modulated by basic fibroblast growth factor (bFGF) through regulation of the PDGF receptor alpha on these cells. A related receptor c-kit is also expressed on progenitors at a discrete stage preceding differentiation. Neurons are signalling progenitors to become oligodendrocytes and not type 2 astrocytes. A later precursor - reacting with the 04 antibody - is multipolar, much less migratory, and give rise to resting stem cells which persist in the adult CNS. When moving along the oligodendrocyte pathway, the cells synthesize different isoforms of TGF beta which can modulate their own growth in an autocrine manner. In the adult human white matter a small population of glial cells express genes characteristic of an early stage of oligodendrocyte differentiation such as the PDGF receptor alpha and myelin basic protein (MBP) mRNAS containing exon 2 information. Cultures of adult human white matter also contains immature cells characterized as preoligodendrocytes. bFGF is a potent stimulator of regeneration of processes by adult human oligodendrocytes and can cause dedifferentiation in these cells. We are presently investigating whether such cells can be induced to divide and differentiate by purified factors and neuronal derived signals in vivo and in vitro. These studies may pave the way to the design of strategies to enhance remyelination in demyelinating diseases. Another factor crucial in successful myelin repair is the ability of cells with remyelinating potential to migrate toward lesions. We found that grafted glial cells in rodents are able to migrate through the normal white matter toward a demyelinating lesion and are now investigating the specific signals that trigger this migration.
