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CORD-19:02a37452d5c5906b46021fbfa99a96df71704b65 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-55 Sentence denotes What roles do growth factors play in CNS remyelination?
T2 57-65 Sentence denotes Abstract
T3 68-277 Sentence denotes The substantial advances that have been made during the last two decades on the developmental biology of the oligodendrocyte lineage have undoubtedly provided a major impetus to the study of CNS remyelination.
T4 278-408 Sentence denotes Specific markers have been recognised that allow the identification of distinctive phenotypes within the oligodendrocyte lineage .
T5 409-642 Sentence denotes Armed with these markers, it has been possible to elucidate the lineage relationships between these phenotypes both in vitro and during development, and to describe the migratory, proliferative and differentiation properties of each.
T6 643-919 Sentence denotes This has led to a conceptual framework of oligodendrogliogenesis that in recent years has been applied to studies on the dynamics of the oligodendrocyte lineage in adulthood, and the need to generate replacement oligodendrocytes and new myelin sheaths following demyelination.
T7 920-1467 Sentence denotes Using stage-specific markers to identify cells associated with spontaneous remyelination, and to obtain purified population of oligodendrocyte lineage cells for transplantation into experimental models of demyelination, the long-standing debate about the origin of remyelinating oligodendrocytes is being resolved in favour of the adult oligodendrocyte progenitor (OP) (Groves et al., 1993; Warrington et al., 1993; Keirstead and Blakemore, 1997; Car-roll et al., 1998; Crang et al., 1998; Redwine and Armstrong, 1998; Levine and Reynolds, 1999) .
T8 1468-1710 Sentence denotes This chapter reviews the role that growth factors play in orchestrating the behaviour of the adult OP in remyelination, and discusses how this information may be relevant to formulating new ways of promoting remyelination in clinical disease.
T9 1711-1851 Sentence denotes Areas of complete remyelination contain more oligodendrocytes than were present in the same area of white matter before it was demyelinated.
T10 1852-2188 Sentence denotes Remyelination must therefore involve the generation of new oligodendrocytes, regardless of whether previously myelinating mature oligodendrocytes that survive within an area of demyelination can generate new myelin sheaths, a view for which experimental data provides little support (Keirstead and Blakemore, 1997; Crang et al., 1998) .
T11 2189-2443 Sentence denotes The weight of evidence from experimental models of remyelination indicates that OPs are the major and probably exclusive source of the new cells (Godfraind et al., 1989; Gensert and Goldman, 1997; Cenci di Bello et al., 1999; Levine and Reynolds, 1999) .
T12 2444-2610 Sentence denotes A critical early event in remyelination is the recruitment of OPs, a process that involves their proliferation and migration both within and into a demyelinated area.
T13 2611-2859 Sentence denotes The zone of recruitment from intact white matter around the area of demyelination appears to be very narrow , although may be greater if the demyelination is close to a germinal region such as the sub-ventricular zone (Nait-Oumesmar et al., 1999) .
T14 2860-3029 Sentence denotes Once recruited, the OPs then need to engage the de-myelinated axons and differentiate into myelinating oligodendrocytes for the process of remyelination to be completed.
T15 3030-3231 Sentence denotes Thus, the key sequence of events effecting the oligodendrocyte lineage during remyelination is the proliferation and migration of OPs, and finally their d@erentiation into myelinating oligodendrocytes.
T16 3232-3394 Sentence denotes Clearly, an essential component in understanding how remyelination works is the identification of the factors involved in governing these three properties of OPs.
T17 3395-3627 Sentence denotes Here again, developmental studies have pointed the way, revealing a number of growth factors that effect the proliferation, migration and differentiation of neonatal OPs during myelination (reviewed in Woodruff and Franklin, 1997) .
T18 3628-3826 Sentence denotes These studies have led investigators to ask whether adult OPs, the cell responsible for mediating remyelination, are similarly influenced by growth factors both in vitro, and more recently, in vivo.
T19 3827-4063 Sentence denotes Tissue culture studies on OPs isolated from the adult rodent CNS indicate that PDGF, FGF-2, GGF-2 and NT-3 are all mitogenic for these cells (Wolswijk et al., 1991; Wolswijk and Noble, 1992; Engel and Wolswijk, 1996; Shi et al., 1998) .
T20 4064-4221 Sentence denotes In some instances, this effect can be synergistic, such as the combination of PDGF with either FGF-2 (Wolswijk and Noble, 1992) or GGF-2 (Shi et al., 1998) .
T21 4222-4351 Sentence denotes PDGF and FGF-2 also increase the motility of OPs, and again the combination of these two growth factors has a synergistic effect.
T22 4352-4499 Sentence denotes On the basis of these effects, one could imagine these factors, singly or in combination, being involved in the recruitment phase of remyelination.
T23 4500-4649 Sentence denotes The ability of FGF-2 to inhibit differentiation of adult OPs is also consistent with its playing a role in OP recruitment (Gard and Pfeiffer, 1993) .
T24 4650-4736 Sentence denotes What then of growth factors that induce differentiation of OPs into myelinating cells?
T25 4737-4939 Sentence denotes Here there is less direct evidence from adult-derived OPs, but one can make a case based on observations using neonatal derived OPs and transgenics that both IGF-I and TGF-fll might have such an effect.
T26 4940-5265 Sentence denotes During post-natal myelination, maximal levels of IGF-I immediately precede periods of active myelination (Carson et al., 1983; Rotwein et al., 1988; Bach et al., 1991) , while the phenotype of transgenic mice that over-express IGF-I also indicate a key role in myelin sheath formation (Carson et al., 1993; Ye et al., 1995) .
T27 5266-5458 Sentence denotes Similarly, in vitro studies on the effects of TGF-81 on OPs suggest that it may have a role in inducing differentiation, by inhibiting mitogen-driven OP proliferation (Mckinnon et al., 1993) .
T28 5459-5527 Sentence denotes Growth factor expression during remyelination in experimental models
T29 5528-5855 Sentence denotes Having described growth factor effects on adult OPs in tissue culture, a next step is to establish whether there are changes in the expression levels of any of these growth factors in experimental models of remyelination, and whether these patterns are consistent with the predicted roles in OP recruitment and differentiation.
T30 5856-5991 Sentence denotes This has been addressed using a number of different models, and using both protein and mRNA detection methods (summarised in Table 1 ).
T31 5992-6220 Sentence denotes In an early study, Komoly and colleagues used in situ hybridisation and immunocytochemistry to detect changes in IGF-I expression during remyelination of cuprizone-induced demyelination of the mouse brain (Komoly et al., 1992) .
T32 6221-6369 Sentence denotes The levels of IGF-I mRNA were highest at the beginning of remyelination and gradually decreased as MBP mRNA accumulated and remyelination proceeded.
T33 6370-6585 Sentence denotes The IGF-I mRNA was localised to astrocytes, although the possibility that macrophages, a feature of this and other demyelinating lesions (Morel1 et al., 2000) , might also be a source was not specifically addressed.
T34 6586-6771 Sentence denotes A similar association between IGF-I expression and remyelination was subsequently demonstrated using a cryogenic demyelinating lesion (Yao et al., 1995b) and in EAE (Liu et al., 1994) .
T35 6772-7036 Sentence denotes In cryogenic lesions, evidence was presented that in the early stages of repair most of the IGF mRNA expression was in areas from which GFAP mRNA was absent, indicating that there are cells other than astrocytes that are a source of IGF-I in remyelinating lesions.
T36 7037-7164 Sentence denotes Another murine model has been used to demonstrate the expression of PDGF-A during remyelination (Redwine and Armstrong, 1998) .
T37 7165-7334 Sentence denotes In this model, demyelination is induced by intracranial injection of mouse hepatitis virus (strain A-59), a coronavirus that causes glial cell lysis following infection.
T38 7335-7934 Sentence denotes This results in widespread demyelination throughout the Komoly et al., 1992 Yao et al., 1995b Liu et al., 1994 Hinks and Franklin, 1999 Copelman et al., 2000 Redwine and Armstrong, 1998 Hinks and Franklin, 1999 Copelman et al., 2000 Liu et al., 1998 Hinks and Franklin, 1999 Copelman et al., 2000 Tourbah et al., 1992 Hinks and Franklin, 1999 Copelman et al., 2000 Copelman et al., 2000 Hinks and Franklin, 1999 Hinks and Franklin, 1999 Hinks and Franklin, 1999 Copelman et al., 2000 Copelman et al., 2000 neuraxis that does not start to remyelinate until virus is cleared at 4 weeks post-injection.
T39 7935-8217 Sentence denotes Redwine and Armstrong have shown that there is an increase in the number of cells expressing PDGF-A mRNA during the early stages of remyelination when there was extensive proliferation of OPs, and that there is a corresponding increase in PDGF-A immunoreactivity during this period.
T40 8218-8385 Sentence denotes The PDGF-A immunoreactivity was localised to GFAP+ astrocytes, suggesting that these cells are a primary source of PDGF-A chain-containing dimers during remyelination.
T41 8386-8551 Sentence denotes A third rodent model used to study growth factor expression is that which involves the direct injection of the demyelinating chemical lysolecithin into white matter.
T42 8552-8803 Sentence denotes Injection of lysolecithin creates a focal area of demyelination characterised by the presence of demyelinated axons, loss of myelin protein mRNAs and a robust macrophage response (Blakemore, 1976; Woodruff and Franklin, 1999; Ousman and David, 2000) .
T43 8804-8993 Sentence denotes This is followed by a stereotypic pattern of remyelination that is determined by the species, sex and age of the animal (Blakemore, 1978; Gilson and Blakemore, 1993; Shields et al., 1999) .
T44 8994-9293 Sentence denotes In young adult rat spinal cord, new myelin sheaths do not appear in the lesion until 10 days after lesion induction, shortly after the reappearance of MBP and PLP mRNA transcripts within the area of demyelination, and by 21 days the lesion is extensively remyelinated (Woodruff and Franklin, 1999) .
T45 9294-9557 Sentence denotes One can therefore divide the remyelination process into a recruitment phase when the lesion is repopulated with remyelinating cells, which gives way around day 10 to a differentiation phase when the recruited cells differentiate into myelinating oligodendrocytes.
T46 9558-9753 Sentence denotes Using this model, we have examined the mRNA expression of a range of growth factors that influence the behaviour of perinatal and adult oligodendrocyte progenitors in vitro or during development.
T47 9754-9945 Sentence denotes Although we could find no change in the expression levels of GGF-2, NT-3 or CNTF, there were distinctive patterns of expression of PDGF-A, FGF-2, IGF-I and TGF-PI (Hinks and Franklin, 1999) .
T48 9946-10190 Sentence denotes The levels of expression of IGF-I and TGF-PI gradually rise during the recruitment phase, peak at 10 days and then gradually decline during the differentiation phase, returning to control levels at 28 days when the lesion is fully remyelinated.
T49 10191-10345 Sentence denotes By contrast, both PDGF-A and FGF-2 have much lower and more restricted levels of expression than either IGF-I or TGF-l31 with different temporal profiles.
T50 10346-10569 Sentence denotes Both PDGF-A and FGF-2 rapidly reach peak levels at the beginning of the recruitment phase, which in the case of PDGF-A are sustained throughout remyelination but for FGF-2 gradually decline during the differentiation phase.
T51 10570-10843 Sentence denotes By comparing the growth factor mRNA expression patterns with those of astrocyte and macrophage markers, our data suggest that reactive astrocytes produce increased levels of all four mRNAs, and that the macrophages produce particularly high levels of IGF-I and TGF-bl mRNA.
T52 10844-11192 Sentence denotes The significant contribution that macrophages are making to the expression of IGF-I mRNA largely determines the expression profile of this growth factor and of TGF-pl, and differs from the observation made by Komoly and co-workers using the cuprizone model, which suggested that astrocytes were the principal source of IGF-I (Komoly et al., 1992) .
T53 11193-11277 Sentence denotes What roles for growth factors can we infer from the in vitro and expression studies?
T54 11278-11549 Sentence denotes The predictions that can be made for specific growth factor roles on the basis of their in vitro effects on adult OPs are largely upheld by the observations summarised in the previous section on the expression patterns of growth factors in a range of experimental models.
T55 11550-11803 Sentence denotes Although it is not always possible to separate distinct recruitment and differentiation phases, and in many situations the two events are occurring concurrently during much of the remyelination process, nevertheless, particular associations can be made.
T56 11804-12110 Sentence denotes For example, PDGF and FGF-2, both of which promote proliferation and motility of adult OPs, and might therefore be expected to be involved in mediating OP recruitment, are expressed early during the repair process when expansion of OPs is occurring (Redwine and Armstrong, 1998; Hinks and Franklin, 1999) .
T57 12111-12319 Sentence denotes FGF-1, whose effects on adult OPs have not been directly assessed but may have similar, albeit less potent effects to FGF-2, is also expressed during the early stages of remyelination (Tourbah et al., 1992) .
T58 12320-12620 Sentence denotes IGF-I and TGF-l3 1, whose in vitro effects suggest they may be involved in the differentiation phase of remyelination, have increased levels of expression occurring at a time when differentiated remyelinating oligodendrocytes appear within the lesion (Komoly et al., 1992; Hinks and Franklin, 1999) .
T59 12621-12913 Sentence denotes Thus, one can propose a schema of remyelination in which the initial proliferation of OPs is driven by astrocyte-derived PDGF-A and FGF, and that the subsequent differentiation of the recruited OPs is triggered by the expression of astrocyte and macrophage derived IGF-I and TGF-PI (Fig. 1) .
T60 12914-13119 Sentence denotes If this schema were true then one would predict that in situations where the rate of remyelination is slowed then there ought to be corresponding changes in the expression patterns of these growth factors.
T61 13120-13396 Sentence denotes For example, slowing of remyelination might arise from a delayed increase in expression of the putative recruitment factors PDGF-A and FGF-2, or from a delay in the maximal expression of the putative differentiation factors IGF-I and TGF-bl, or a combination of both of these.
T62 13397-13659 Sentence denotes In a recent study, we have tested this prediction by comparing the growth factor mRNA expression in rapidly remyelinating lysolecithin lesions made in young adult rats with the expression in slowly remyelinating lesions in old adult rats (Shields et al., 1999) .
T63 13660-13827 Sentence denotes This study revealed delay in the onset of increased PDGF-A mRNA expression and a delay in the peak expression in the IGF-I and TGF-pl mRNA (Hinks and Franklin, 2000) .
T64 13828-13922 Sentence denotes Both these results are consistent with our prediction and add support for the proposed schema.
T65 13923-14007 Sentence denotes Although most studies support the proposed schema, this is not universally the case.
T66 14008-14272 Sentence denotes Copelman and colleagues have recently published data on growth factor mRNA expression in an intriguing brain aggregate tissue culture model of remyelination that are curiously at variance with the data from in vivo models of remyelination (Copelman et al., 2000) .
T67 14273-14471 Sentence denotes In this model, the increase in PDGF-A mRNA, detected by RT-PCR, occurs after an increase in IGF-I and FGF-2 mRNA levels, a sequence of change that is difficult to reconcile with the proposed schema.
T68 14472-14742 Sentence denotes One interpretation of this data is that while PDGF may be required for OP generation in the in vivo models of remyelination there may not be a similar requirement in the aggregate model where sufficient numbers of OPs may remain in the aggregate following demyelination.
T69 14743-15053 Sentence denotes Another possibility is that PDGF is only one of a number of factors, including FGF-2 and possibly other as yet unrecog- nised factors, that are required for OP expansion and indicated that growth factor signalling is an importhat OP recruitment can proceed in its absence. tant part of efficient remyelination.
T70 15054-15366 Sentence denotes Although plausible hypotheses regarding the roles of growth factors can be devised on the basis of expression studies such as those described, the evidence that they do indeed have an important determining role comes from studies in which changes in remyelination can be induced by changing growth factor levels.
T71 15367-15469 Sentence denotes Such evidence has come from studies in which growth factors have been both supplemented and inhibited.
T72 15470-15721 Sentence denotes The latter has been achieved using a pharmacological antagonist, trapidil, which decreased the extent of oligodendrocyte remyelination of lysolecithin-induced demyelination in rats following systemic delivery (McKay et al., 1997; McKay et al., 1998) .
T73 15722-15955 Sentence denotes Despite being widely described as a PDGF antagonist, it was not possible to infer a specific role for PDGF since other data (including our own unpublished observations) indicate that trapidil inhibits a range of other growth factors.
T74 15956-16199 Sentence denotes The pharmacological approach suffers from its lack of specificity, but nevertheless, the trapidil experiments If remyelination can be inhibited by removing growth factor effects is it possible to enhance remyelination by adding growth factors?
T75 16200-16369 Sentence denotes This is inherently harder to achieve for a variety of reasons including the possibility that growth factor levels are saturated even though remyelination is sub-optimal.
T76 16370-16615 Sentence denotes It is also worth noting that there are very few rodent models of demyelination where remyelination is incomplete, meaning that most studies will, at best, be able to demonstrate an enhancement of the rate rather than the extent of remyelination.
T77 16616-16825 Sentence denotes Even so, this approach has attracted some attention because of the possibility that growth factor-based therapies may be helpful in promoting remyelination in demyelinating diseases such as multiple sclerosis.
T78 16826-17170 Sentence denotes The first attempts to enhance remyelination using growth factors stemmed from the work on IGF-I expression in the cuprizone, cryogenic and EAE models, and involved daily intravenous or sub-cutaneous delivery of IGF-I after induction of EAE by passive transfer of MBP-reactive T-lymphocytes in Lewis rats (Yao et al., 1995a (Yao et al., , 1996 .
T79 17171-17434 Sentence denotes The results of these studies showed that IGF-I was not only able to reduce the number of demyelinating foci, but also changed a number of parameters that were associated with remyelination, including the number of PLP mRNA expressing cells present within lesions.
T80 17435-17716 Sentence denotes Since the IGF-I was delivered systemically and not directly into a demyelinating lesion, it was unclear whether the effects of IGF-I delivery were due to direct effects on oligodendrocyte lineage cells, or an indirect effect via a change in, for example, the inflammatory response.
T81 17717-17994 Sentence denotes Subsequent studies indicated that the observed effects were probably due to the latter given the reduced damage to the blood-brain barrier and the reduction in the number of inflammatory cells within the CNS responsible for demyelination (Liu et al., 1997 (Liu et al., , 1998 .
T82 17995-18186 Sentence denotes It is likely therefore that the improvement in remyelination was not a result of direct stimulation of OL cells by IGF-I, but rather that it was able to proceed in a less hostile environment.
T83 18187-18294 Sentence denotes A similar approach was used to assess the remyelination-enhancing properties of GGF-2, an adult OP mitogen.
T84 18295-18441 Sentence denotes GGF-2 was delivered systemically by daily sub-cutaneous injection to mice in whom chronic relapsing EAE had been induced (Cannella et al., 1998) .
T85 18442-18570 Sentence denotes Similar to the IGF-I studies in rat EAE, the GGF-2 treated animals showed clinical improvements compared to the control animals.
T86 18571-18733 Sentence denotes Moreover, the increase in expression of MBP exon 2-containing mBNAs together with histopathological data, indicated improved remyelination in the treated animals.
T87 18734-18930 Sentence denotes However, since the GGF-2 was delivered systemically, it remains unclear whether the observed effects of GGF-2 were as a result of direct effects on oligodendrocyte lineage cells within the lesion.
T88 18931-19075 Sentence denotes A strategy for promoting CNS remyelination by direct delivery of growth factors to the CNS has recently been reported by McTigue et al. (1998) .
T89 19076-19223 Sentence denotes In this study, fibroblasts engineered to produce NT-3, BDNF, CNTF, NGF and FGF-2 were transplanted into contusion lesions in adult rat spinal cord.
T90 19224-19368 Sentence denotes In the lesions that received NT-3 and BDNF supplementation, there was increased axonal regrowth and a corresponding increase in the myelination.
T91 19369-19651 Sentence denotes Important though these results undoubtedly are, it is not entirely resolved whether the increase in myelination is simply a reflection of their being more 'axon' available for myelination or whether there is a direct effect of the two neurotrophins on oligodendrocyte lineage cells.
T92 19652-19916 Sentence denotes The effects of NT-3 on adult OPs equivocal and difficult to reconcile with the effects described since it would appear to be mitogenic for cells derived from the brain (Shi et al., 1998) , but not for those derived from the spinal cord (Engel and Wolswijk, 1996) .
T93 19917-20004 Sentence denotes There is little known about the effects of BDNF on adult oligodendrocyte lineage cells.
T94 20005-20103 Sentence denotes The feasibility of growth factor-based therapies for promoting remyelination in multiple sclerosis
T95 20104-20314 Sentence denotes The failure of remyelination, which becomes an increasingly characteristic feature of multiple sclerosis as the disease progresses, has stimulated the quest for methods by which remyelination might be promoted.
T96 20315-20497 Sentence denotes Transplantation of myelinogenic cells is one approach in which much effort has been invested and one that gets ever closer to clinical implementation (Blakemore and Franklin, 2000) .
T97 20498-20582 Sentence denotes An alternative approach is to try and enhance or reactivate intrinsic remyelination.
T98 20583-20754 Sentence denotes The notion that growth factors may provide a means of achieving has often been discussed (e.g. McMorris and Mckinnon, 1996; Woodruff and Franklin, 1997; Wolswijk, 1998a) .
T99 20755-20999 Sentence denotes Although much remains to be learnt about the precise roles of growth factors in remyelination, it is becoming clear from the existing experimental data that the process requires the sequential expression of different growth factor combinations.
T100 21000-21101 Sentence denotes Moreover, the timing of this sequence critically determines the rate and efficiency of remyelination.
T101 21102-21331 Sentence denotes An implication of this is that the effects of growth factor supplementation will be determined by the stage of remyelination at which they are administered and that inappropriate supplementation may actually impede remyelination.
T102 21332-21479 Sentence denotes For example, if a lesion were failing to remyelinate because of a shortage of OPs, then recruitment-associated growths factors would be beneficial.
T103 21480-21648 Sentence denotes On the other hand, differentiation-associated growth factors would be disadvantageous by inducing premature differentiation at the expense of the required OP expansion.
T104 21649-21992 Sentence denotes Conversely, if a lesion was replete with OPs that were failing to differentiate, a situation that exists in at least some non-remyelinating MS lesions (Wolswijk, 1998a,b) , then differentiation-associated growth factors may allow remyelination to proceed to completion, while recruitment-associated growth factors would exacerbate the problem.
T105 21993-22182 Sentence denotes The potential for inhibiting myelination by growth factor deliv-ery has recently been demonstrated in developmental myelination of the rat anterior medullary vellum (Goddard et al., 1999) .
T106 22183-22385 Sentence denotes With current technology, it seems unlikely that it would be possible to know what growth factor strategy would be required for a particular plaque or for a particular patient without recourse to biopsy.
T107 22386-22649 Sentence denotes It is also imperative to gain a deeper understanding of the effects of different growth factors on oligodendrocyte lineage cells derived from the adult human CNS, an issue for which recent advances in isolation protocols will undoubtedly help (Roy et al., 1999) .
T108 22650-22923 Sentence denotes Without this information, coupled with a more detailed analysis of growth factor roles that will emerge from experimental data, the handful of studies that have described expression of a number of growth factors in MS lesions are difficult to assess (Gveric et al., 1999) .
T109 22924-23183 Sentence denotes Thus, although the concept of growth factor therapies for promoting remyelination has much to commend it, there are still substantial issues to be resolved before a rational approach based on an understanding of the mechanisms of remyelination can be devised.
T110 23184-23486 Sentence denotes It is perhaps worth remembering that although the role of growth factors in regeneration of other tissue, such as skin, has progressed considerably further than our understanding of growths factors in remyelination, there are few widely used therapies for wound healing based on growth factor delivery.
T111 23487-23726 Sentence denotes Nevertheless, there can be little doubt that a clearer path to achieving therapeutic remyelination will emerge from a careful dissection of the roles performed by growth factors and the other key mediators of this important repair process.
T112 23727-24213 Sentence denotes Abbreviations BDNF CNS CNTF EAE FGF GFAP GGF IGF MBP MOG NT-3 OL brain-derived neurotrophic factor central nervous system ciliary neurotrophic factor experimental allergic encephalomyelitis fibroblast growth factor glial fibrillary acidic protein glial growth factor insulin-like growth factor myelin basic protein myelin oligodendrocyte glycoprotein neurotrophin-3 oligodendrocyte lineage OP oligodendrocyte progenitor PDGF platelet-derived growth factor TGF transforming growth factor