Glia Disease and Repair-Remyelination.

Glia Disease and Repair—Remyelination Robin J.M. Franklin1 and Steven A. Goldman2,3 1 Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB3 0ES, United Kingdom 2 Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642 3 University of Copenhagen Faculty of Medicine, Copenhagen 2200, Denmark Correspondence: ; The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, although this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granular neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet, remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this review, we will review the biology of remyelination, including the cells and signals involved; describe when remyelination occurs and when and why it fails and the consequences of its failure; and discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain. IDENTIFYING REMYELINATION emyelination is the process in which new myelin sheaths are restored to axons that have lost their myelin sheaths as a result of primary demyelination. Primary demyelination is the term used to describe the loss of myelin from an otherwise intact axon and should be distinguished from myelin loss secondary to axonal loss—a process called Wallerian degeneration or, misleadingly, secondary demyelination. Remyelination is sometimes referred to as myelin repair. However, this term suggests a damaged but otherwise intact myelin internode be- R ing “patched up,” a process for which there is no evidence and which does not emphasize the truly regenerative nature of remyelination, in which the prelesion cytoarchitecture is substantially restored. Remyelinated tissue very closely resembles normally myelinated tissue but differs in one important aspect—the newly generated myelin sheaths are typically shorter and thinner than the original myelin sheaths. When myelin is initially formed in the peri- and postnatal period, there is a striking correlation between axon diameter and myelin sheath thickness and length, which is less apparent in remyelination. Instead, myelin sheath thickness and Editors: Ben A. Barres, Marc R. Freeman, and Beth Stevens Additional Perspectives on Glia available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a020594 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020594 1 R.J.M. Franklin and S.A. Goldman length show little increase with increasing axonal diameter, with the result that the myelin is generally thinner and shorter than would be expected for a given diameter of axon (Fig. 1). Although some remodeling of the new myelin internode occurs, the original dimensions are rarely regained (Powers et al. 2013). The relationship between axon diameter and myelin sheath is expressed as the G ratio, which is the fraction of the axonal circumference to the axon plus myelin sheath circumference. The identi- A 5 dpl YFP GFAP B YFP PLP 21 dpl Figure 1. Genetic fate mapping of oligodendrocyte precursor cells (OPCs) reveals them to be the principal source of remyelinating oligodendrocytes. Using Cre-lox fate mapping in transgenic mice, it is possible to show that platelet-derived growth factor receptor a (PDGFRA)/NG2-expressing OPCs (green YFPþ) in the adult CNS respond to chemically induced focal demyelination of the ventral spinal cord white matter (inset in A) by proliferation and migration and are abundant within the area of damage, defined here by immunohistochemistry for the astrocyte marker GFAP (red), at 5 d postlesion (dpl) (A). At 21 dpl, when the lesion has undergone complete remyelination, green YFPþ OPC-derived remyelinating oligodendrocytes can be seen producing new myelin sheaths around the demyelinated axons, detected by expression of the myelin protein PLP (red) (B) (see Zawadzka et al. 2010). 2 fication of abnormally thin myelin sheaths (greater than normal G ratio) remains the “gold standard” for unequivocally identifying remyelination, and is most reliably identified in resin-embedded tissue, viewed by light microscopy following toluidine blue staining, or by electron microscopy. This effect is obvious when large diameter axons are remyelinated, but is less clear with smaller diameter axons, such as those of the corpus callosum, in which G ratios of remyelinated axons can be difficult to distinguish from those of normally myelinated axons (Stidworthy et al. 2003). How is the relationship between myelin parameters and axon size established in myelination and why is it disengaged in remyelination? In the peripheral nervous system (PNS), axonally expressed neuregulin (NRG)1-type III plays a key role. Reduced expression results in a thinner myelin sheath (increased G ratio), whereas overexpression leads to a thicker than expected myelin sheath (decreased G ratio) (Michailov et al. 2004). In the central nervous system (CNS) however, the role of neuregulins in controlling myelin sheath length and thickness is less clear (Brinkmann et al. 2008), although they may play a role in activity-dependent remyelination. The factors that govern the G ratio in remyelination would seem to be distinct from those operating in developmental myelination, such that an explanation for the increased G ratio in remyelination remains elusive. For example, overexpression of NRG leads to hypermyelination in development but not during remyelination (Brinkmann et al. 2008). Similarly, activation of the Akt pathway, which results in thicker than expected myelin sheaths in development (Flores et al. 2008), does not result in thicker remyelinated sheaths following demyelination in the adult (Harrington et al. 2010). One hypothesis is that, whereas the myelinating oligodendrocyte associates with a dynamically changing axon to achieve its full length and diameter, the remyelinating oligodendrocyte engages an axon that is comparatively static, having already reached its mature size (Franklin and Hinks 1999). As a result, the remyelinating oligodendrocyte is not subjected to the same dynamic stresses encountered Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020594 Remyelination by the developmentally myelinating oligodendrocyte. REMYELINAT (...truncated)