Invited Review Growth Factors and Remyelination in The

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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. cell cycle time and reduced migration rate in vitro The final stage of oligodendrocyte maturation involves compared to its perinatal forebear (Wolswijk and Noble, the orderly expression of the myelin proteins 2',3' 1989), which has lead to suggestions that the cyclic nucleotide 3'-phosphorylase (CNP), myelin basic proliferative and migratory capacity of the adult protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte progenitor in vivo may be insufficient associated glycoprotein (MAG) (Monge et al. to account for the extent of myelin formation during 1986), myelin oligodendrocyte glycoprotein (MOG) remyelination. However, when adult oligodendrocyte (Mattieu and Amiguet, 1990), and, in vivo, myelin progenitors are exposed to platelet-derived growth factor associated/oligodendrocytic basic protein (MOBP) (PDGF) and fibroblast growth factor-2 (FGF-2) in vitro (Holz et aI., 1996), and the elaboration of myelin their proliferation and migration rate are significantly sheaths (reviewed by Pfeiffer et aI., 1993) (see increased (Wolswijk and Noble, 1992), suggesting that Fig. 1). such phenotypic alterations may occur in vivo in the 461 Growth factors and eNS remyelination

presence of appropriate environmental cues. denotes a fully differentiated phenotype, although cells Whether newly-generated cells in remyelination are expressing this marker in vitro may be very different in derived from adult oligodendrocyte progenitors, their behaviour from the myelinating oligodendrocyte of perineuronal satellite oligodendrocytes (Ludwin, 1979a) adult white matter. The evidence that mature oligo or mature oligodendrocytes that have de-differentiated dendrocytes are able to divide in vivo is equivocal. remains somewhat controversial. Since it is implicit in Uptake of [3H]-thymidine has been observed in this model that the events of remyelination are oligodendrocytes attached to myelin sheaths (Ludwin essentially similar to developmental myelinogenesis, it and Bakker, 1988), but this is not a wholly convincing would seem logical to suggest that remyelinating indicator of mitosis since [3H]-thymidine uptake also oligodendrocytes are recruited from the pool of occurs following DNA damage. Furthermore, it is oligodendrocyte precursors that is known to be present questionable whether the proliferative capacity of these w ithin the CNS (ffrench-Constant and Raff, 1986; cells, if they proliferate at all, is sufficient to bring about Wolswijk and Noble, 1989; Scolding et ai, 1995). extensive remyelination (reviewed by Ludwin, 1987a). However, an alternative view is that remyelinating Finally, in the x-irradiation paradigm one would predict oligodendrocytes are generated from mature oligo that, if remyelinating oligodendrocytes were generated dendrocytes (reviewed by Wood and Bunge, 1991; from mature oligodendrocytes, the lesion would get reviewed by Wood and Mora, 1993), implying that progressively larger as oligodendrocytes adjacent to the mature oligodendrocytes have the capacity to de area of demyelination would die as a result of attempting differentiate and re-enter the cell cycle. In vitro studies to divide in response to remyelination signals within the have shown that oligodendrocytes expressing GalC lesion. The fact that this does not occur argues against proliferate (Wood and Bunge, 1986) and may de significant proliferation of mature oligodendrocytes in differentiate (Wood and Bunge, 1991) following response to demyelination. exposure to naked axons, although it is possible that the The essential feature of the models of remyelination increased numbers of pro-oligodendrocytes observed described above is that remyelinating oligodendrocytes may have arisen from contaminating ol igodendrocyte are a population of cells generated de novo by mitosis in progenitors rather than GaIC+ oligodendrocytes. It has response to the demyelinating insult. A wholly different been assumed in these studies that expression of GalC concept of remyelination is that it is brought about by

immature oligodendrocyte pre-progenitor 0 -2A pro-oligodendroblast progenitor oligodendrocyte 0 10, 01, 0 4 01. 04. PSA·NCA M A2B5. GaIC, CNP, 04, A007 PDGF·aR ? GDJ PLP, MBP, MAG GalC A2B5 PDGF·aR (MaG, MOBP)' CNP GDJ NG2

® ---. f ---.

PDGF - S,M PDGF - S,M,C PDGF - S,M IFG-I - S,M IFG-I -S IFG-I - S,M IFG-I -S,M NT-3 - S NT-3 - S FGF1 - M NT3 - S CNTF -S CNTF-S FGF2 - M FGF2 - M, (S) LlF-S LlF-S 11-2 - M 11-6 - S 11-6 - S NT-3 - S,M FGF1 - (S) TGF-AM

Fig. 1. Effects of growth factors on proliferation, motility and survival in the oligodendrocyte lineage. C: chemoattractant; M: mitogen; AM: anti-mitotic effect; S: survival factor. Recognised markers for stages in the lineage are in italics. 0: effects for which equivocal data exists. *: markers associated with myelinating cell in vivo. 462 Growth factors and eNS remyelination

oligodendrocytes that survive within areas of de at which point PDGFa-receptor expression is lost myelination and regenerate new myelin sheaths. This (Barres et aI., 1992; Ellison and de Vellis, 1994), whilst raises the question whether mature oligodendrocytes are insulin-like growth factors (IGFs) increase the survival able to re-initiate the myelination programme without of both oligodendrocyte progenitors and oligodendro undergoing cell division. Studies modelling de cytes (Barres et aI., 1992). In addition to IGFs, neuro myelination in vitro have indicated that oligodendrocytes trophin-3 (NT-3), ciliary-neurotrophic factor (CNTF), are able to regenerate myelin-like membranes LIF and interleukin-6 (IL-6) are survival factors for (Fressinaud and Vallat, 1994), which suggests that oligodendrocytes (Barres et ai., 1993; Louis et aI., 1993). surviving oligodendrocytes may be able to remyelinate Furthermore, CNTF is able to protect oligodendrocytes in vivo. Evidently, this prediction is dependent on the from the toxic effects of tumour necrosis factor (Louis et demonstration of oligodendrocyte survival within areas aI., 1993; D'Souza et aI., 1996). of demyelination and of a correlation between the degree A variety of growth factors are potent mitogens for of oligodendrocyte survival and the potential to undergo oligodendrocyte progenitors, and therefore may act remyelination. MOG has proved to be a useful oligo during remyelination to stimulate the proliferation of dendrocyte marker in this regard, since it is expressed on remyelinating oligodendrocytes. PDGF is a potent the surface of oligodendrocytes that have survived mitogen for oligodendrocyte progenitors isolated from destruction of their myelin sheaths (Ludwin, 1990) and the perinatal (Noble et aI., 1988; Richardson et aI., 1988) thus can be used to identify surviving oligodendrocytes. and adult CNS (Wolswijk et aI., 1991), and prevents Evidence in support of this view comes from studies that their premature differentiation into oligodendrocytes have identified mature oligodendrocytes within lesions (Noble et aI., 1988; Richardson et aI., 1988). Loss of formed during the early course of multiple sclerosis responsiveness to the mitogenic effects of PDGF occurs (Bri.ick et aI., 1994; Ozawa et aI., 1994). In contrast to prior to the loss of cell surface PDGFa-receptors from this, another study reported that oligodendrocytes were newly differentiated oligodendrocytes (Hart et aI., 1992) almost completely absent from fresh multiple sclerosis possibly due to changes in signal transduction lesions (Prineas et aI., 1993), implying that there is mechanisms or changes in the expression of NG2 considerable heterogeneity in MS lesions. proteoglycan (Nishiyama et a!., 1996a). Finally, the In summary, the balance of evidence tends to chemoattractive effect of PDGF on oligodendrocyte suggest that immature oligodendrocytes, that are progenitors in vitro (Armstrong et aI., 1990) suggests probably derived from oligodendrocyte precursors, are that it may playa role in directing the migration of largely responsible for remyelination, although surviving remyelinating oligodendrocytes towards areas of oligodendrocytes may be involved to a limited extent. demyelination. Fibroblast growth factor-2 (FGF-2) is a potent Growth factors and oligodendrocyte remyelination in mitogen for both oligodendrocyte progenitors the eNS (McKinnon et aI., 1990, Fressinaud and Vallat, 1994) and oligodendrocytes (Besnard et aI., 1989; Grinspan et Based on the models of remyelination described a!., 1993), and exerts an inhibitory effect on their above, one can predict that that the efficiency of differentiation (McKinnon et aI., 1990). Indeed it has remyelination may be enhanced in its early stages by been reported that FGF-2 treatment induces mature factors that promote the survival, proliferation and oligodendrocytes to de-differentiate in vitro (Grinspan et migration of remyelinating oligodendrocytes, and, at aI., 1993), an observation which lends support to the later stages, by factors that enhance myelin synthesis. hypothesis that remyelinating oligodendrocytes may be There are several lines of evidence suggesting that generated from mature stages of the oligodendrocyte growth factors may be able to influence these processes. lineage. However, these results must be interpreted with Studies on the effects of growth factors on the some caution as it is possible that contaminating pre development of the oligodendrocyte lineage (Fig. 1) progenitors may have given rise to the increased have provided much indirect evidence that growth numbers of oligodendrocyte progenitors observed, and factors playa role in remyelination, since the that FGF-2 may actually induce oligodendrocyte death remyelinating oligodendrocyte seems to be similar to the in some circumstances (Scolding and Compston, 1995; oligodendrocyte progenitor. Survival of cells of the Muir and Compston 1996). IGF-I and interleukin 2 (IL- oligodendrocyte lineage, which is likely to be an 2) have been reported to stimulate proliferation of oligo important factor in determining the availability of dendrocyte progenitors and promote their maturation remyelinating oligodendrocytes and their ability to (Benveniste and Merrill, 1986; McMorris and Dubois migrate into lesions (Franklin et aI. , 1996), is regulated Dalq; 1988, McMorris et a!., 1993). However, other by a number of growth factors. PDGF, which is studies were unable to show a clear mitogenic effect of abundantly expressed in the developing CNS (Yeh et aI., IGF-I on oligodendrocyte progenitors (Barres et a!., 1991) and is secreted by astrocytes (Richardson et aI., 1992). In the pig, nerve growth factor (NGF) stimulates 1988), promotes the survival of cells of the oligodendro proliferation of GaIC+ oligodendrocytes in vitro cyte lineage from the pre-progenitor stage (Grinspan and (Althaus et aI., 1992), but the growth factors that are Franceschini, 1995) until the pro-oligodendrocyte stage mitogens for rodents have no effect. On a cautionary 463 Growth factors and eNS remyelination

note, no mitogens for proliferating stages of the human same cells and also by astrocytes (Gehrmann et aI., oligodendrocyte lineage have been identified to date 1996). In lysolecithin-induced demyelination in the rat (Scolding et ai., 1995). spinal cord, there is increased expression of PDGF In addition to their individual actions described during the period when recruitment of remyelinating above, combinations of growth factors have been shown oligodendrocytes is believed to occur, and the putative to exert co-operative effects on oligodendrocyte PDGF antagonist trapidil inhibits the spontaneous progenitors. When perinatal oligodendrocytes are treated remyelination of these lesions, observations which are with a combination of PDGF and FGF-2 they are highly suggestive that PDGF does indeed playa role in prevented from differentiating and undergo sustained remyelination (McKay et aI., 1997). Furthermore, proliferation (Bogler et ai., 1990). This is believed to be astrocytes that are similar to those that have been shown due to an upregulation of PDGFa-receptors by FGF-2 to produce PDGF in vitro, promote remyelination by (McKinnon et aI., 1990; Nishiyama et aI., 1996a). host oligodendrocytes when transplanted into ethidium Treatment of adult oligodendrocyte progenitors with the bromide-induced lesions in the adult rat spinal cord same combination of growth factors results in a similar (Franklin et ai., 1990). Finally, the precedent of using inhibition of differentiation and causes a marked exogenous growth factors to alter recovery has been increase in their rate of division and migration established in an EAE model in which treatment with (Wolswijk and Noble, 1992; Engel and Woswijk, 1996), IGF-I reduces clinical severity and lesion size, and which is a potential mechanism whereby large pools of increases MBP mRNA expression (Yao et ai., 1995, remyelinating oligodendrocytes may be generated in 1996). However the improvement may be due to anti vivo. Similarly NT-3, which exerts a modest pro inflammatory effects of IGF-I rather than a direct effect liferative effects on its own, acts co-operatively with on oligodendrocytes to promote remyelination. PDGF to promote clonal expansion of ol igodendrocyte pro-genitors derived from the neonatal optic nerve Conclusion (Barres et ai., 1994), although no mitogenic effect is observed on oligodendrocyte progenitors isolated from The effects of growth factors on the developing the adult spinal cord (Engel and Wolswijk, 1996). oligodendrocyte lineage are suggestive of a number of As well as their various effects on the early stages of ways in which they may potentially promote re the oligodendrocyte lineage, a number of studies have myelination, especially in the context of the model of indicated that growth factors are able to influence myelin remyelination considered above. The events that may synthesis during development, suggesting that they may potentially be modulated by growth factors during have similar effects during remyelination. Transgenic remyelination are the generation of immature oligo mice that overexpress IGF-I in the CNS show increased dendrocytes by mitosis and their survival, the migration myelin content that is not simply due to increased brain of remyelinating oligodendrocytes into areas of size (Carson et aI., 1993), increased myelin sheath demyelination, the regeneration of oligodendrocyte thickness relative to axon diameter and increased levels processes and the expression of myelin protein genes. of MBP and PLP mRNA (Ye et aI., 1995). Over The expression of growth factors in demyelinating expression of IGF binding protein 1 (IGFBP-1), which lesions strongly suggests that they are involved in inhibits the actions of IGF-I by reducing its bio spontaneous remyelination, and therefore delivery of availability, causes a corresponding reduction in these exogenous growth factors to poorly-repairing de parameters. Moreover, PDGF (Fressinaud et ai., 1996) myelination may be a viable strategy to promote and FGF-2 (Fressinaud and Vallat, 1994, Fressinaud et remyelination in the CNS. aI., 1995) promote the recovery of myelin-like membranes in vitro following membrane disruption by References lysolecithin, although FGF-2 reduces myelin gene expression and myelin compaction. Finally in the pig, Althaus H.H., Kloppner S., Schmidt-Schultz T. and Schwartz P. (1992). 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