Histol Histopathol (1997) 12: 459-466 Histology and Histopathology lnvited Revie w Growth factors and remyelination in the CNS R.H. Woodruff and R.J.M. Franklin Departrnent of Clinical Veterinary Medicine and MRC Centre for Brain Repair, University of Carnbridge, Cambridge, UK Summary. It is now well established that there is an multiple sclerosis (MS) (Prineas and Connell, 1979; inherent capacity within the central nervous system Prineas et al., 1989, 1993; Raine and Wu, 1993). (CNS) to remyelinate areas of white matter that have However, remyelination is not universaily consistent or undergone demyelination. However this repair process is sustained, and incomplete remyelination has been not universally consistent or sustained, and persistent reported in gliotoxic lesions of old animals (Gilson and demyelination occurs in a number of situations, most Blakemore, 1993), in certain forms of experimental notably in the chronic multiple sclerosis (MS) plaque. allergic encephalitis (EAE) (Raine et al., 1974), and is a Thus there is a need to investigate ways in which myelin hall-mark feature of the chronic MS plaque. Thus, there deficits within the CNS rnay be restored. One approach is considerable interest in developing ways in which to this problem is to investigate ways in which the persistently demyelinated axons rnay be reinvested with inherent remyelinating capacity of the CNS rnay be myelin sheaths in order to restore secure conduction of stimulated to remyelinate areas of long-term de- impulses. Efforts to address this problem have focussed myelination. The expression of growth factors, which mainly on the use of glial cell transplantation techniques are known to be involved in developmental myelino- to deliver exogenous glial cells into the CNS of hypo- genesis, in areas of demyelination strongly suggests that myelinating myelin mutants (Lachapelle et al., 1984; they are involved in spontaneous remyelination. Duncan et al., 1988, reviewed by Gumpel et al., 1989; Therefore delivery of exogenous growth factors into Duncan, 1996) and into gliotoxic lesions (Blakemore areas of persistent demyelination is a potential and Crang, 1988; Groves et al., 1993) and thereby therapeutic strategy for stimulating remyelination. This replace myelin deficits (reviewed by Franklin, 1993). An review will discuss the evidence that growth factors rnay alternative approach to transplantation is to investigate have a role in promoting CNS remyelination by ways in which the endogenous remyelinating capacity of enhancing the survival and stimulating the proliferation the CNS rnay be enhanced in situations where and recruitment of remyelinating oligodendrocytes. spontaneous remyelination has failed, such as the chronic MS plaque (Grinspan et al., 1994). Evidently, Key words: Remyelination, Oligodendrocyte, Oligo- this requires a detailed understanding of the cellular and dendrocyte Progenitor, Growth Factors, CNS molecular mechanisms that are involved in re- myelination in order to identify logical strategies for therapeutic intenrention. This review wili discuss current lntroduction views on the mechanisms of remyelination by oligodendrocytes and the evidence that growth factors Most central nervous system (CNS) axons are rnay be potentially useful agents for augmenting the enwrapped by myelin sheaths, which are synthesised and inherent remyelinating response. maintained by oligodendrocytes. Loss of myelin sheaths, or demyelination, results in impaired impulse conduction The oligodendrocyte lineage in development and neurological dysfunction (reviewed by Smith, 1994). There is, however, an inherent capacity within the CNS An understanding of the oligodendrocyte lineage is to remyelinate denuded axons. This repair process, important since remyelination shows many similarities which rnay be extensive, occurs in a number of to developmental myelinogenesis and, further- experimental situations (reviewed by Ludwin, 1987a,b), more, growth factors have a variety of effects on including the gliotoxic models (reviewed by Blakemore different stages of the oligodendrocyte lineage. During et al., 1983) and in naturally-occurring diseases such as development oligodendrocyte progenitors are generated within germina1 zones, such as the subventricular zone - Offprint requests to: Rachel H. Woodruff, Departrnent of Clinical (Curtis et al., 1988; Levine and Goldman, 1988; Levison Veterinary Medicine and MRC Centre for Brain Repair, University of and Goldman, 1993) and ventral spinal cord (Warf et al., Cambridge, Madingley Road, Cambridge CB3 OES, UK 1991; Yu et al., 1994), from where they migrate into Growth factors and CNS remyelination both white and grey matter to reach their final Current hypotheses on oligodendrocyte re- destinations in the CNS. Oligodendrocyte progenitors myelination in the central nervous system are small, round process-bearing cells that rnay be identified in vivo by a number of specific markers, Remyelination was first described over thirty years including NG2 proteoglycan (Levine et al., 1993; ago in the adult cat spinal cord following CSF barbotage Nishiyama et al., 1996b), platelet-derived growth factor (Bunge et al., 1961). Despite vigorous investigation, the (PDGF) a-receptor (Pringle et al., 1992; Ellison and de precise mechanisms of remyelination are still Vellis, 1994), DM-20 (Timsit et al., 1995), and incompletely understood at present. In general, it is quisqualate-stimulated uptake of cobalt (Fulton et al., widely accepted that the remyelinating oligodendrocyte 1992). Historically, they are referred to in the literature is a proliferative cell of immature phenotype. as 0-2A progenitors on the basis of their bipotentiality The first evidence that remyelination is associated in vitro (Raff et al., 1983; Behar et al., 1988; Levi et al., with the proliferation of cells of immature phenotype 1988). Although they constitutively differentiate into was described in early studies on cuprizone-induced oligodendrocytes, they rnay be induced to differentiate demyelination (Blakemore, 1973; Ludwin, 1979b). into A2B5+ GFAP+ type-2 astrocytes in the presence of These observations are supported by other studies using 10% fetal calf serum (Raff et al., 1983), ciliary JHM virus-induced demyelination showing that neurotrophic factor (CNTF) (Hughes et al., 1988; Lillien remyelination involves proliferation of cells of the et al., 1988; Kahn and De Vellis, 1994), leukaemia oligodendrocyte lineage (Herndon et al., 1977). inhibitory factor (LIF) (Kahn and De Vellis, 1994; Gard However, the long interval between administration of et al., 1995) and oncostatin M (Gard et al., 1995). [3~]-thymidineand perfusion prevented identification of However this nomenclature is slightly misleading since the phenotype of the dividing cells. More recently, it does not appear that type-2 astrocytes are generated similar findings have been described in a model of foca1 during normal development in vivo (Skoff, 1990; Fulton experimentally-induced demyelination in the cat optic et al. 1992), or if they do occur it is only rarely (Levison nerve (Carro11 and Jennings, 1994). These morphological and Goldman, 1993), although they rnay occur in certain observations have been supported by immunocyto- pathological conditions (Barnett et al., 1993; Franklin et chemical studies which have identified an early increase al., 1995; reviewed by Franklin and Blakemore, 1995). in the number of oligodendrocyte progenitors expressing The perinatal oligodendrocyte progenitor gives rise to a 04, (Godfraind et al., 1989) and GD3 (Reynolds and population of oligodendrocyte progenitors that is present Wilkin, 1993) in demyelinating lesions. Furthermore in the adult CNS (ffrench-Constant and Raff, 1986; spontaneous remyelination of gliotoxic lesions is Wolswijk and Noble, 1989; Wren et al., 1992; Scolding inhibited following exposure to doses of x-irradiation et al., 1995). Adult oligodendrocyte progenitors show that kill mitotic cells (Blakemore and Patterson, 1978), bipotentiality in vitro, but have a longer cell cycle time providing further evidence that cell division is necessary and slower migratory rate than their perinatal forebears for remyelination. On the basis of the evidence described and have a slightly different antigenic phenotype. It is above, it rnay be postulated that immature oligodendro- widely believed that newly-generated oligodendrocytes cytes are generated in the vicinity of areas of in remyelination are derived from this pool of cells in demyelination by mitosis, before migrating into these response to demyelination. areas where they engage axons and synthesise myelin The next stage in the oligodendrocyte lineage is an sheaths in a similar fashion to developmental myelino- intermediate stage known as the pro-oligodendrocyte genesis. The highly proliferative and migratory that has a multipolar morphology and expreses the behaviour of perinatal oligodendrocyte progenitors both surface antigens pro-oligodendroblast antigen (POA) in vitro (Small et al., 1987; Wolswijk and Noble, 1989) (Bansal et al., 1992) and sulfatide (Bansal et al., 1989) and during development (Curtis et al., 1988; Levine and recognised by the monoclonal antibody 04 (Sommer Goldman, 1988; Hardy and Reynolds, 1991; Reynolds and Schachner, 1982). Differentiation into oligodendro- and Wilkin, 1991) is consistent with this view. One of cytes is characterised by the development of a complex the criticisms of this hypothesis is that the adult morphology, the expression of galactocerebroside (Gal oligodendrocyte