Epistemic_Statements  

CORD-19:02a37452d5c5906b46021fbfa99a96df71704b65 JSONTXT 9 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 409-642 Epistemic_statement 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.
T2 920-1467 Epistemic_statement 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) .
T3 1468-1710 Epistemic_statement 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.
T4 1852-2188 Epistemic_statement 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) .
T5 2189-2443 Epistemic_statement 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) .
T6 2611-2859 Epistemic_statement 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) .
T7 3232-3394 Epistemic_statement denotes Clearly, an essential component in understanding how remyelination works is the identification of the factors involved in governing these three properties of OPs.
T8 3628-3826 Epistemic_statement 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.
T9 3827-4063 Epistemic_statement 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) .
T10 4064-4221 Epistemic_statement 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) .
T11 4352-4499 Epistemic_statement denotes On the basis of these effects, one could imagine these factors, singly or in combination, being involved in the recruitment phase of remyelination.
T12 4500-4649 Epistemic_statement 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) .
T13 4737-4939 Epistemic_statement 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.
T14 4940-5265 Epistemic_statement 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) .
T15 5266-5458 Epistemic_statement 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) .
T16 5459-5527 Epistemic_statement denotes Growth factor expression during remyelination in experimental models
T17 5528-5855 Epistemic_statement 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.
T18 5856-5991 Epistemic_statement denotes This has been addressed using a number of different models, and using both protein and mRNA detection methods (summarised in Table 1 ).
T19 6370-6585 Epistemic_statement 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.
T20 6586-6771 Epistemic_statement 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) .
T21 6772-7036 Epistemic_statement 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.
T22 8218-8385 Epistemic_statement 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.
T23 8994-9293 Epistemic_statement 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) .
T24 9754-9945 Epistemic_statement 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) .
T25 10570-10843 Epistemic_statement 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.
T26 10844-11192 Epistemic_statement 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) .
T27 11193-11277 Epistemic_statement denotes What roles for growth factors can we infer from the in vitro and expression studies?
T28 11278-11549 Epistemic_statement 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.
T29 11550-11803 Epistemic_statement 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.
T30 11804-12110 Epistemic_statement 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) .
T31 12111-12319 Epistemic_statement 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) .
T32 12320-12620 Epistemic_statement 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) .
T33 12621-12908 Epistemic_statement 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.
T34 12914-13119 Epistemic_statement 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.
T35 13120-13396 Epistemic_statement 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.
T36 13828-13922 Epistemic_statement denotes Both these results are consistent with our prediction and add support for the proposed schema.
T37 13923-14007 Epistemic_statement denotes Although most studies support the proposed schema, this is not universally the case.
T38 14273-14471 Epistemic_statement 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.
T39 14472-14742 Epistemic_statement 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.
T40 14743-15015 Epistemic_statement 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.
T41 15054-15366 Epistemic_statement 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.
T42 15367-15469 Epistemic_statement denotes Such evidence has come from studies in which growth factors have been both supplemented and inhibited.
T43 15722-15955 Epistemic_statement 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.
T44 15956-16199 Epistemic_statement 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?
T45 16200-16369 Epistemic_statement 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.
T46 16370-16615 Epistemic_statement 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.
T47 16616-16825 Epistemic_statement 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.
T48 17171-17434 Epistemic_statement 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.
T49 17435-17716 Epistemic_statement 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.
T50 17717-17994 Epistemic_statement 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 .
T51 17995-18186 Epistemic_statement 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.
T52 18734-18930 Epistemic_statement 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.
T53 19369-19651 Epistemic_statement 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.
T54 19652-19916 Epistemic_statement 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) .
T55 19917-20004 Epistemic_statement denotes There is little known about the effects of BDNF on adult oligodendrocyte lineage cells.
T56 20005-20103 Epistemic_statement denotes The feasibility of growth factor-based therapies for promoting remyelination in multiple sclerosis
T57 20104-20314 Epistemic_statement 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.
T58 20498-20582 Epistemic_statement denotes An alternative approach is to try and enhance or reactivate intrinsic remyelination.
T59 20583-20677 Epistemic_statement denotes The notion that growth factors may provide a means of achieving has often been discussed (e.g.
T60 20755-20999 Epistemic_statement 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.
T61 21102-21331 Epistemic_statement 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.
T62 21332-21479 Epistemic_statement denotes For example, if a lesion were failing to remyelinate because of a shortage of OPs, then recruitment-associated growths factors would be beneficial.
T63 21480-21648 Epistemic_statement denotes On the other hand, differentiation-associated growth factors would be disadvantageous by inducing premature differentiation at the expense of the required OP expansion.
T64 21649-21992 Epistemic_statement 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.
T65 21993-22182 Epistemic_statement 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) .
T66 22183-22385 Epistemic_statement 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.
T67 22386-22649 Epistemic_statement 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) .
T68 22650-22923 Epistemic_statement 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) .
T69 22924-23183 Epistemic_statement 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.
T70 23184-23486 Epistemic_statement 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.
T71 23487-23726 Epistemic_statement 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.