SummaryOligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated. Even there, all OPs were dividing and generating new OLs and myelin at a rate higher than can be explained by first-time myelination of naked axons. We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths. The latter would predict that average internode length should decrease with age. Consistent with that, we found that adult-born OLs elaborated much shorter but many more internodes than OLs generated during early postnatal life.

After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells. The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes. These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system.

Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and postnatal development of OLs have been well‐studied and many features of the process have been described, including the origin, migration, proliferation, and differentiation of precursor cells. Less clear is the extent to which OLs and damaged/dysfunctional myelin are replaced following injury to the adult CNS. OLs and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer’s disease, spinal cord injury, Parkinson’s disease, ischemia, and hypoxia. However, studies of certain conditions to date have detected spontaneous OL replacement. This review will summarize current information on adult OL progenitors, mechanisms that contribute to OL death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.

Summary Cycling glial precursors - “NG2-glia” - are abundant in the developing and mature central nervous system (CNS). During development they generate oligodendrocytes. In culture, they can revert to a multipotent state, suggesting that they might have latent stem cell potential that could be harnessed to treat neurodegenerative disease. This hope has been subdued recently by a series of fate mapping studies that cast NG2-glia as dedicated oligodendrocyte precursors in the healthy adult CNS - though rare neuron production in the piriform cortex remains a possibility. Following CNS damage, the repertoire of NG2-glia expands to include Schwann cells and possibly astrocytes – but so far not neurons. This confirms the central role of NG2-glia in myelin repair. The realization that oligodendrocyte generation continues throughout normal adulthood has seeded the idea that myelin genesis might also be involved in neural plasticity. We review these developments, highlighting areas of current interest, contention and speculation.

The adult mammalian brain and spinal cord contain glial precursors that express platelet-derived growth factor receptor ␣ subunit (PDGFRA) and the NG2 proteoglycan. These "NG2 cells" descend from oligodendrocyte precursors in the perinatal CNS and continue to generate myelinating oligodendrocytes in the gray and white matter of the postnatal brain. It has been proposed that NG2 cells can also generate reactive astrocytes at sites of CNS injury or demyelination. To test this we examined the fates of PDGFRA/NG2 cells in the mouse spinal cord during experimental autoimmune encephalomyelitis (EAE)-a demyelinating condition that models some aspects of multiple sclerosis in humans. We administered tamoxifen to Pdgfra-CreER