New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination

Abstract

Regeneration of myelin (remyelination) in the central nervous system (CNS) has long been thought to be principally mediated by newly generated oligodendrocytes, a premise underpinning therapeutic strategies for demyelinating diseases, including multiple sclerosis (MS). Recent studies have indicated that oligodendrocytes that survive demyelination can also contribute to remyelination, including in MS, but it is unclear how remyelination by surviving oligodendrocytes compares to that of newly generated oligodendrocytes. Here we studied oligodendrocytes in MS, and also imaged remyelination in vivo by surviving and new oligodendrocytes using zebrafish. We define a previously unappreciated pathology in MS, myelination of neuronal cell bodies, which is recapitulated during remyelination by surviving oligodendrocytes in zebrafish. Live imaging also revealed that surviving oligodendrocytes make very few new sheaths, but can support sheath growth along axons. In comparison, newly made oligodendrocytes make abundant new sheaths, properly targeted to axons, and exhibit a much greater capacity for regeneration.