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(American Journal of Pathology. 2004;164:1673-1682.)
© 2004 American Society for Investigative Pathology

Oligodendrocytes and Progenitors Become Progressively Depleted within Chronically Demyelinated Lesions

Jeffrey L. Mason^*, Arrel Toews, Janell D. Hostettler, Pierre Morell, Kinuko Suzuki, James E. Goldman^* and Glenn K. Matsushima^||

From the Department of Pathology and the Center for Neurobiology and Behavior,^* Columbia University, New York, New York; and the University of North Carolina Neuroscience Center, Curriculum in Neurobiology, Department of Biochemistry and Biophysics, Department of Pathology and Laboratory Medicine, Program in Molecular Biology and Biotechnology and Department of Microbiology and Immunology,|| University of North Carolina, Chapel Hill, North Carolina

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. 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. 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. Furthermore, the oligodendrocyte progenitors also become progressively depleted within the lesion, which appears to contribute to the chronic demyelination. 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. 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. 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.

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