The oligodendrocyte progenitor response to demyelination /

by Vana, Adam C

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. Factors that may influence remyelination are important, as denuded axons have impaired neurotransmission and increased vulnerability to transection. The general belief is that remyelination requires robust oligodendrocyte progenitor (OP) amplification prior to remyelination. Myelin transcription factor 1 (Myt1) influences OP proliferation, differentiation, and myelin gene transcription in vitro. The potential of Myt1 to influence OP responses leading to remyelination was examined using murine hepatitis virus (MHV) induced demyelination. Myt1 expression was dramatically increased in lesioned white matter. Cells expressing Myt1 proliferated extensively during active demyelination and early remyelination, and Myt1 was observed predominantly in OPs. Increased expression of Myt1 was found within MHV lesions and in MS tissue adjacent to and within lesions. These results suggest a potential role for Myt1 in oligodendrocyte lineage cell regeneration in response to acute demyelination. 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 iii 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. iv The Oligodendrocyte Progenitor Response to Demyelination by Adam C. Vana Thesis/dissertation submitted to the Faculty of the Neuroscience Program Uniformed Services University of the Health Sciences In partial fulfillment of the requirements for the degree of Doctor of Philosophy 2006 v