Histol Histopathol (1997) 12: 459-466 Histology and 001: 10.14670/HH-12.459 Histopathology http://www.hh.um .es From Cell Biology to Tissue Engineering Invited Review Growth factors and remyelination in the eNS R.H. Woodruff and R.J.M. Franklin Department of Clinical Veterinary Medicine and MRC Centre for Brain Repair, University of Cambridge, Cambridge, UK Summary. It is now well established that there is an multiple sc lerosis (MS) (Prineas and Connell , 1979; inherent capacity within the central nervous sys tem Prineas e t a I. , 1989, 1993; Ra ine a nd Wu, 1993). (CNS) to remyelinate areas of w hite matter that have However, remyelinati on is not universall y consistent or undergone demyelination. However this repair process is s us ta ined , and incomple te rem yelina ti o n has been not universall y consistent or sustained, and persistent reported in gliotoxic lesions of old animals (Gilson and demyelinati on occurs in a number of situations, most Blakemo re, 1993), i n certain forms of experimental notably in the chronic multiple sclerosis (MS) plaque. allergic encephalitis (EAE) (Raine et aI. , 1974), and is a Thus there is a need to investigate ways in which myelin hall-mark fea ture of the chronic MS plaque. Thus, there deficits within the CNS may be restored. One approach is considerable interest in developing ways in w hic h to this proble m is to investi gate ways in whic h the persistently demyelinated axons may be reinvested with inherent remyelinating capacit y of the C NS may be myelin sheaths in order to restore secure conduction of s timula te d to re m yelin a te a reas of lo ng -te rm d e ­ impulses. Efforts to address this problem have focussed m yelinat ion. The expression of growth factors, w hi ch mainly on the use of glial cell transpl antation techniques are known to be involved in developmental myelino­ to deliver exogenous gli al cell s into the CNS of hypo­ genesis, in areas of demyelination strongly suggests that myelinating myelin mutants (Lachapell e et aI. , 1984; they a re involved in s po nta neous re m yelin a ti o n . Duncan et aI. , 1988, reviewed by Gumpel et aI. , 1989; Therefore deli very of exogenous g rowth facto rs into Duncan, 1996) and into gli otoxic lesions (Blakemo re a reas of pe rsiste nt d e m ye lin a ti o n is a po te ntia l and Crang, 1988; G roves et a I. , 1993) a nd thereby therapeutic strategy fo r stimulating remyelination. This repl ace myelin deficits (reviewed by Franklin, 1993). An review will discuss the evidence that growth factors may alternati ve approach to transpl antati on is to investi gate have a ro le in pro m o ting C NS re m ye lina ti o n b y ways in which the endogenous remyelinating capacity of enhancing the survival and stimulating the pro liferation the C NS m ay be e nh a nced in s it ua ti o ns w he re and recruitment of remyelinating oligodendrocytes. s po ntaneous re myelinati o n has fa il ed , s uc h as the chroni c MS pl aque (Grinspan et aI. , 1994). Evidently, Key words: Remyelinatio n, Oligodendrocyte, Oligo­ this requires a detailed understanding of the cellular and dend rocyte Progenitor, Growth Factors, CNS m o lecul a r m echa ni s m s t ha t a re involved in re ­ myelinati on in ord er to identify logical strategies for therapeutic intervention. This review w ill discuss current Introduction v ie w s o n the m echa nis ms o f re m yelin a tio n b y o ligodendrocytes and the evidence that growth factors Most centra l ne rvous sys te m (CNS) axons are may be potentiall y 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 dysfuncti on (reviewed by Smith, 1994). T here is, however, an inherent capacity within the CNS An understanding of the oligodendrocyte lineage is to remyelinate denuded axons. This repair process, important since re myelination shows many similarities w hi c h m ay be ex te ns ive , occurs in a numbe r of to d evelo pme nta l m ye linogenesis a nd , f urthe r­ experimental situations (reviewed by Ludwin, 1987a,b), mo re , g rowth facto rs have a vari e ty of effects o n including the gliotoxic models (reviewed by Blakemore different stages of the oligodendrocyte lineage. During et aI. , 1983) and in naturall y-occurring diseases such as development oligodendrocyte progenitors are generated within germinal zones, such as the subventricular zone Offprint requests to : Rachel H. Wood ruff, Department of Clinical (Curtis et aI. , 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 aI. , Cambridge, Madingley Road , Cambridge CB3 OES, UK 1991 ; Yu et a I. , 1994), from where they migrate into 460 Growth factors and eNS 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 may be identified in vivo by a number of specific markers, Remyelination was first described over thirty years including NG2 proteoglycan (Levine et aI., 1993; ago in the adult cat spinal cord following CSF barbotage Nishiyama et aI. , 1996b), platelet-derived growth factor (Bunge et aI., 1961). Despite vigorous investigation, the (PDGF) a-receptor (Pringle et aI. , 1992; Ellison and de precise mechanisms of remyelination are still Yellis, 1994), DM-20 (Timsit et aI. , 1995), and incompletely understood at present. In general, it is quisqualate-stimulated uptake of cobalt (Fulton et aI. , 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 aI. , 1983; Behar et aI., 1988; Levi et aI., with the proliferation of cells of immature phenotype 1988). Although they constitutively differentiate into was described in early studies on cuprizone-induced oligodendrocytes, they may 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 aI. , 1983), ciliary JHM virus-induced demyelination showing that neurotrophic factor (CNTF) (Hughes et aI. , 1988; Lillien remyelination involves proliferation of cells of the et aI. , 1988; Kahn and De Yellis, 1994), leukaemia oligodendrocyte lineage (Herndon et aI., 1977). inhibitory factor (UF) (Kahn and De YelIis, 1994; Gard However, the long interval between administration of et aI., 1995) and oncostatin M (Gard et aI., 1995). [3H]-thymidine and 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 focal 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 (Carroll and Jennings, 1994). These morphological and Goldman, 1993), although they may occur in certain observations have been supported by immunocyto­ pathological conditions (Barnett et aI. , 1993; Franklin et chemical studies which have identified an early increase aI. , 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 aI., 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 aI. , 1992; Scolding inhibited following exposure to doses of x-irradiation et aI., 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 may 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 expresses the behaviour of perinatal oligodendrocyte progenitors both surface antigens pro-oligodendroblast antigen (POA) in vitro (Small et aI., 1987; Wolswijk and Noble, 1989) (Bansal et aI., 1992) and sulfatide (Bansal et aI., 1989) and during development (Curtis et aI., 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 progenitor has a markedly increased C) (Raff et aI., 1978), and the cessation of cell division.