Oligodendrocyte Progenitor Response to Demyelination

摘要

In multiple sclerosis (MS), demyelination results in impaired axon conduction and functional deficits. Remyelination is often observed early in the MS disease course, but over time becomes limited. The general belief is that remyelination requires robust oligodendrocyte progenitor (OP) amplification prior to remyelination. With MS being a chronic disease we were interested in the responses that occurred following chronic demyelination. Studies using the chronic cuprizone model of demyelination display limited remyelination, a depleted pool of OPs, and decreased oligodendrocytes. We now show that after chronic demyelination apoptosis continues even after cessation of cuprizone to evaluate means to promote remyelination. Overexpression of platelet-derived growth factor-A (PDGF-A) was tested with chronic cuprizone demyelination in hPDGF-A transgenic (tg) mice. Remyelination was improved in hPDGF-A tg mice during recovery after chronic demyelination. OP density and proliferation increased only transiently in hPDGF-A tg mice during acute demyelination but not during chronic demyelination or recovery. Importantly, hPDGF-A tg mice had increased oligodendrocyte regeneration associated with reduced apoptosis during recovery. The effect of increased PDGF-A is likely as a survival factor during the regeneration of oligodendrocytes and remyelination, as preventing apoptosis of oligodendrocytes may be important not only during acute demyelination but also during chronic demyelination. Overall, we found that following demyelination Myt1 may have a potential role in the regeneration of oligodendrocyte lineage cells, whereas the overexpression of PDGF-A appears to enhance survival of newly differentiated myelinating oligodendrocytes.