Nerve regeneration in the peripheral and central nervous systems

The critical role of Schwann cells in supporting nerve regeneration in the peripheral nervous system (PNS) and the contrasting inability of oligodendrocytes to do so in the central nervous system (CNS) has concerned neuroscientists since the seminal work of Ramon y Cajal (Cajal, 1928). Cajal’s power of observation and capacity to capture the essence of, and to interpret his light microscopic slides of normal and injured nerves in the PNS and CNS, established these now well accepted concepts. Oligodendrocytes in the CNS share the capacity of Schwann cells to myelinate axons although their pattern of myelination is quite different; each oligodendrocyte protrudes cytoplasmic processes that enwrap and form myelin sheaths around several of the axons within the CNS whilst, each Schwann cell wraps around a single peripheral axon with the cell body being included in the wrap. In the rat, for example, an individual oligodendrocyte in the optic nerve forms as many as 20 myelin internodes (Ransom et al. 1991). The axons that are disconnected from the cell bodies or soma of the injured neurons in both nervous systems undergo Wallerian degeneration: the axons degenerate and the myelin fragments (Stoll et al. 2002; Vargas & Barres, 2007). The denervated Schwann cells proliferate and extend long cytoplasmic processes. The cells and their processes cross surgical sites of reunion of proximal and distal nerve stumps and, they line the endoneurial tubes as the Bands of Büngner to support and guide growing axons to denervated targets (Büngner, 1891; Cajal, 1928; Fu & Gordon, 1997). However, there is a limited time window in which the Schwann cells express growth-associated genes and, in turn, support axon regeneration (Fu & Gordon, 1995; Hoke et al. 2006; Gordon et al. 2011). The Schwann cell numbers decline and the cells undergo atrophy, progressively failing to support nerve regeneration (Fu & Gordon, 1995; Vuorinen et al. 1995a; Gordon et al. 2011). In the CNS, on the other hand, a programmed cell death is initiated when oligodendrocytes lose axonal contact, many of the cells entering into an ‘atrophy-like resting state’ (Vargas & Barres, 2007). Wallerian degeneration is not robust in the CNS as it is in the PNS: that the poor clearance of the myelin debris is likely to be an important contributing factor to failure of CNS nerves to regenerate after injury is illustrated by the remaining debris 3 years after degeneration of human CNS axons (Buss et al. 2004). The oligodendrocytes fail to support nerve growth in the CNS; the retraction bulbs of the axons proximal to CNS lesions (Erturk et al. 2007) and the inhibitory molecules of the myelin, including myelin-associated glycoprotein and NOG0 expressed on the glial cells, preclude regeneration, in contrast to the Schwann cells’ support of nerve regeneration in the PNS (Fenrich & Gordon, 2004). This review introduces the topics that were covered by each of four contributors, Jessen, Bunge, Karimi-Abdolrezaee, and Chan, to the symposium entitled ‘Axon regeneration and remyelination in the peripheral and central nervous systems’ at the Physiology Society meeting in Cardiff in July 2015. Their topics are reviewed in four accompanying articles in this issue of the Journal of Physiology (Alizah & Karimi-Abdolrezaee, 2016; Bunge, 2016; Chan et al., 2016; Jessen & Mirsky, 2016). The developmental stages of the myelination of peripheral nerves, a very active subject of research over many years by Jessen and Mirsky in London, UK, provide the scaffold on which the investigators are currently studying the extent to which the developmental maturation of myelinating and non-myelinating (Remak) Schwann cells is reversed after PNS nerve injury. The switch of the adult myelinating Schwann cell to a non-myelinating growth supportive phenotype involves activation of thousands of genes, many of which are said to be ‘repair-related’ (Arthur-Farraj et al. 2012). Whilst this conversion was previously regarded as a process of dedifferentiation of the mature Schwann cell phenotype to a less mature phenotype (Jessen & Mirsky, 2005), the authors now provide evidence for the activation of a more distinct repair programme in the denervated Schwann cells that differs fundamentally from the development of the cells (Jessen & Mirsky, 2016). The denervated cells, but not immature cells, organize myelin clearance indirectly by macrophage recruitment and directly by autophagy of myelin (Gomez-Sanchez et al. 2015). The repair programme includes the upregulation of genes for transcription factors such as the helix–loop–helix factor, Olig 1, and sonic hedgehog (Shh), which are either not expressed or expressed at very low levels in immature Schwann cells (Arthur-Farraj et al. 2012). The expression of the transcription factor c-jun appears to be a key regulator of the distinct regeneration programme, c-jun directly or indirectly controlling the expression of 180 genes in the denervated Schwann cells and down-regulating myelin-associated genes (Jessen & Mirsky, 2008; Arthur-Farraj et al. 2012). The selective removal of c-jun from Schwann cells in transgenic mice detrimentally reduces survival of both motor and sensory neurons even though the Schwann cells developed and functioned normally in intact nerves (Fontana et al. 2012). After nerve injury in the adult, the denervated Schwann cells, which otherwise would upregulate c-jun, fail to express growth-associated proteins such as neurotrophic factors and cell surface proteins, fail to remove myelin from denervated nerve, do not align normally as the bands of Büngner, and in turn, fail to support axon regeneration. K. R. Jessen and R. Mirsky are currently investigating whether a progressive decline in c-Jun expression in chronically denervated Schwann cells (unpublished data) contributes to the previously demonstrated concurrent decline in the capacity of these cells to support axon regeneration (Fu & Gordon, 1995). The early in vitro work on Schwann cells by Jessen and Mirsky paralleled the in vitro work carried out by Mary and Richard Bunge in St Louis, MO, USA, each isolating the cells, the former concentrating on the development of Schwann cells, and the latter on adult Schwann cells. Over a period spanning from 1975 during their research