Lnvited Revie W Growth Factors and Remyelination in The

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 remyelination 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 progenitor has a markedly increased C) (Raff et al., 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 rnay be insuf ficient 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 al., 1996), and the elaboration of myelin their proliferation and migration rate are significantly sheaths (reviewed by Pfeiffer et al., 1993) (see increased (Wolswijk and Noble, 1992), suggesting that Fig. 1). such phenotypic alterations rnay occur in vivo in the Growth factors and CNS remyelination

presence of appropriate environmental cues. denotes a fully differentiated phenotype, although mlls 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 sateilite 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 [3~]-thymidinehas been observed in this model that the events of remyelination are oligodendrocytes attached to rnyelin 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 [3~]-thymidineuptake 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 within the CNS (ffrench-Constant and Raff, 1986; cells, if they proliferate at ali, is sufficient to bring about Wolswijk and Noble, 1989; Scolding et al, 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 oligodendrocyte are a population of mlls generated de novo by mitosis in progenitors rather than GalCt 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

pre-progenitor O-2A prwligodendroblast oligodendrocyta progenitor 010, 01, 04 04, PSA-NCAM A2BS. GolC. CNP, A007 PDGF-aR ? GD3 GalC PLP, MBP, MAG AZBS PDGF-aR CNP (MOO, MOBP) * GD3 NG2

PDGF - S,M PDGF - S,M,C PDGF - S,M IFG-I - S,M IFG-I - S,M IFG-I - S,M NT-3 - S FGFl - M NT3 - S CNTF - S CNTF - S FGF2 - M FGF2 - M, (S) LIF - S LIF - S 11-2 - M 114 - S 114 - S NT-3 - S,M FGFl - (S) TGF - AM

Flg. 1. Effects of growth factors on proliration, motili and survival in the oligodendmcyte lineage. C: chemoattractant; M: mitogen; AM: anti-rnitoüc eífect; S: survival factor. Recognised markers for stages in the lineage are in italics. 0: effects for which equivoca1 data exists. *: markers associated with myelinating cell in vivo. Growth factors and CNS 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 d., 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 al., 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 d., 1993; Louis et al., 1993). surviving oligodendrocytes rnay 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 al., 1993; D'Souza et al., 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 rnay 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 al., 1988; Richardson et al., 1988) thus can be used to identify surviving oligodendrocytes. and adult CNS (Wolswijk et al., 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 al., 1988; Richardson et al., 1988). Loss of formed during the early course of multiple sclerosis responsiveness to the mitogenic effects of PDGF occurs (Brück et al., 1994; Ozawa et al., 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 al., 1992) almost completely absent from fresh multiple sclerosis possibly due to changes in signal transduction lesions (Prineas et al., 1993), implying that there is mechanisms or changes in the expression of NG2 considerable heterogeneity in MS lesions. proteoglycan (Nishiyama et al., 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 al., 1990) suggests probably derived from oligodendrocyte precursors, are that it rnay play a role in directing the migration of largely responsible for remyelination, although surviving remyelinating oligodendrocytes towards areas of oligodendrocytes rnay 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 CNS (McKinnon et al., 1990, Fressinaud and Vallat, 1994) and oligodendrocytes (Besnard et al., 1989; Grinspan et Based on the models of remyelination described al., 1993), and exerts an inhibitory effect on their above, one can predict that that the efficiency of differentiation (McKinnon et al., 1990). Indeed it has remyelination rnay 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 al., 1993), an observation which lends support to the later stages, by factors that enhance myelin synthesis. hypothesis that remyelinating oligodendrocytes rnay be There are severa1 lines of evidence suggesting that generated from mature stages of the oligodendrocyte growth factors rnay 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 rnay have given rise to the increased have provided much indirect evidence that growth numbers of oligodendrocyte progenitors observed, and factors play a role in remyelination, since the that FGF-2 rnay 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-1 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 al., 1996), is regulated Dalq; 1988, McMorris et al., 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 al., IGF-1 on oligodendrocyte progenitors (Barres et al., 1991) and is secreted by astrocytes (Richardson et al., 1992). In the pig, nerve growth factor (NGF) stimulates 1988), promotes the survival of cells of the oligodendro- proliferation of GalC+ oligodendrocytes in vitro cyte lineage from the pre-progenitor stage (Grinspan and (Althaus et al., 1992), but the growth factors that are Franceschini, 1995) until the pro-oligodendrocyte stage mitogens for rodents have no effect. On a cautionary Growth factors and CNS remyelination

note, no mitogens for proliferating stages of the human same cells and also by astrocytes (Gehrmann et al., oligodendrocyte lineage have been identified to date 1996). In lysolecithin-induced demyelination in the rat (Scolding et al., 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 play a role in prevented from differentiating and undergo sustained remyelination (McKay et al., 1997). Furthermore, proliferation (Bogler et al., 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 al., 1990; Nishiyama et al., 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 al., 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-1 reduces clinical severity and lesion size, and which is a potential mechanism whereby large pools of increases MBP mRNA expression (Yao et al., 1995, remyelinating oligodendrocytes rnay be generated in 1996). However the improvement rnay be due to anti- vivo. Similarly NT-3, which exerts a modest pro- inflammatory effects of IGF-1 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 oligodendrocyte pro-genitors derived from the neonatal optic nerve Conclusion (Barres et al., 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 rnay 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 rnay synthesis during development, suggesting that they rnay potentially be modulated by growth factors during have similar effects during remyelination. Transgenic remyelination are the generation of immature oligo- mice that overexpress IGF-1 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 al., 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 al., 1995). Over- The expression of growth factors in demyelinating expression of IGF binding protein 1 (IGFBP-l), which lesions strongly suggests that they are involved in inhibits the actions of IGF-1 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 al., 1996) myelination rnay be a viable strategy to promote and FGF-2 (Fressinaud and Vallat, 1994, Fressinaud et remyelination in the CNS. al., 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). NGF promotes regeneration of proeesses by mature Nerve growth factor induces proliferation and enhances Rbre oligodendrocytes in vitro (Althaus et al., 1992). regeneration in oligodendrocytes isolated from adult pig brain. More direct evidence of growth factor involvement Neurosci. Lett 135,219-223. in remyelination comes from studies on their expression Armstrong R.C., Ha~athL. and Dubois-Dalq M. (1990). Type 1 in demyelinating lesions, although this area has not astrocytes and oligodendrocyte-type 2 astrocyte glial progenitors been widely researched. Expression of IGF-1 and its migrate towards dffitinct molecules. J. Neurosci. Res. 27,400-407. receptor (IGFR-1) by astrocytes and oligodendrocytes Bansal R., Wamngton A.E., Gard A.L., Ranscht B. and Pfeiffer S.E. respectively is induced during demyelination by (1989). Multiple and novel speciñdies of monoclonal anübodis 01, cuprizone (Komoly et al., 1992), and in EAE (Liu et al., 04, and R-mAb used in the analysis of oligodendrocyte 1994), which suggests that IGF-1 rnay be involved in development. J. Neurosci. Res. 24,548-557. remyelination, especially considering the effects of IGF- Bansal R., Stefansson K. and Pfeier S.E. (1992). Proligodendroblast 1 on the oligodendrocyte development described above. antigen (POA), a developmental antigen expressed by A007104- Moreover, activated microglia and macrophages express positive oligodendrocyte progenitors prior to the appearance of FGF-2 in EAE, whilst its receptor is expressed by the sutíatide and galactocerebroside. J. Neurochem. 58,2221-2229.

Growth factors and CNS remyelination

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