6 Once cuprizone is removed from the diet, the mature oligodendrocytes begin to repopulate the lesion and remyelinate the demyelinated axons. 18 Previously, we reported acute demyelination in C57BL/6 mice 18,19 and the apoptotic death of mature oligodendrocytes within the corpus callosum in mice exposed to cuprizone for a short duration. To test these hypotheses, we used the cuprizone model of chronic demyelination. 2–5 Although the central nervous system (CNS) has the ability to regenerate new oligodendrocytes that remyelinate demyelinated axons following acute demyelination, 6–9 it has been suggested that mature oligodendrocytes are not regenerated within chronically demyelinated lesions due to: 1) the depletion of the oligodendrocyte progenitors 4 2) the inability of the progenitors to proliferate and differentiate within the lesion due to aging 10 or a non-conducive environment 11–14 and/or 3) axon damage 3,15,16 or the inability of chronically demyelinated axons to be remyelinated. Thus, the formation of chronically demyelinated lesions induced by cuprizone appears to be the result of oligodendrocyte depletion within the lesion and not due to the inability of the chronically demyelinated axons to be remyelinated.Īlthough most acutely demyelinated lesions in multiple sclerosis (MS) are remyelinated, 1 the lesions eventually progress to a state of chronic demyelination, characterized by sparse remyelination, few oligodendrocytes, and axon degeneration. However, if adult O4 + progenitors are transplanted into the chronically demyelinated lesion of mice treated with cuprizone for 12 weeks, mature oligodendrocyte regeneration and remyelination occurs after the mice are returned to a normal diet. Interestingly, even if the mice are returned to a normal diet following 12 weeks of exposure to cuprizone, remyelination and oligodendrocyte regeneration does not occur. Furthermore, the oligodendrocyte progenitors also become progressively depleted within the lesion, which appears to contribute to the chronic demyelination. Although there is rapid regeneration of the oligodendrocyte population following an acute lesion, most of these newly regenerated cells undergo apoptosis if mice remain on a cuprizone diet. In this study, we investigated the fate of oligodendrocytes during the progression of a demyelinating lesion to a chronic state and determined whether transplanted adult oligodendrocyte progenitors could remyelinate the chronically demyelinated axons. To understand mechanisms that may underlie the progression of a demyelinated lesion to a chronic state, we have used the cuprizone model of chronic demyelination.

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