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The adult oligodendrocyte can participate in remyelination

I. Duncan,A. Radcliff,Moones Heidari,G. Kidd,B. August,Lauren A. Wierenga

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Remyelination of the CNS is a critical process in restoring function and protecting nerve fibers from degeneration in multiple sclerosis and other demyelinating diseases. It is currently thought that myelin can only be repaired by the generation of new oligodendrocytes from progenitor cells and that remaining mature cells are unable to participate. Here we show, using unique large animal models, including a nonhuman primate, that oligodendrocytes that are partially injured can participate in myelin repair. The capacity of mature oligodendrocytes to remyelinate in demyelinating disease remains unknown, yet it provides an additional cell source for recruitment for myelin repair. Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major therapeutic goal, both to restore function and to protect axons from degeneration. Remyelination is thought to depend on oligodendrocyte progenitor cells, giving rise to nascent remyelinating oligodendrocytes. Surviving, mature oligodendrocytes are largely regarded as being uninvolved. We have examined this question using two large animal models. In the first model, there is extensive demyelination and remyelination of the CNS, yet oligodendrocytes survive, and in recovered animals there is a mix of remyelinated axons interspersed between mature, thick myelin sheaths. Using 2D and 3D light and electron microscopy, we show that many oligodendrocytes are connected to mature and remyelinated myelin sheaths, which we conclude are cells that have reextended processes to contact demyelinated axons while maintaining mature myelin internodes. In the second model in vitamin B12-deficient nonhuman primates, we demonstrate that surviving mature oligodendrocytes extend processes and ensheath demyelinated axons. These data indicate that mature oligodendrocytes can participate in remyelination.

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