No announcement yet.


  • Filter
  • Time
  • Show
Clear All
new posts



    Cell transplantation, myelin repair, and multiple sclerosis
    Christopher Halfpenny , Tracey Benn , and Neil Scolding a, b, c

    Article outline:

    Spontaneous myelin repair in multiple sclerosis
    Oligodendrocyte progenitor cells
    Supplementation of remyelination by glial-cell transplantation
    Cells of the oligodendrocyte lineage
    Schwann cells
    Olfactory glia
    Immortalised cell lines
    Xenogeneic transplantation
    Stem cells
    Promotion of endogenous remyelination
    Application of experimental remyelination biology to patients with multiple sclerosis
    Site of implantation
    The timing of implantation
    Post-therapy management
    Search strategy and selection criteria


    A decade ago, therapeutic strategies to remyelinate the CNS in diseases such as multiple sclerosis had much experimental appeal, but translation of laboratory success into clinical treatments appeared to be a long way off. Within the past 12 months, however, the first patients with multiple sclerosis have received intracerebral implants of autologous myelinating cells. Here we review the clinical and biological problems presented by multiple sclerosis disease processes, and the background to the development of myelin-repair strategies. We attempt to highlight those areas where difficulties have yet to be resolved, and draw on various experimental findings to speculate on how remyelinating therapies are likely to develop in the foreseeable future.


    Dramatic scientific advances in brain repair are never far from the headlines. The transplantation of fetal neurons into the brains of patients with Parkinson's or Huntington's disease, whether appearing to go well or ill, rightly attracts attention. In addition, the highly publicised debate over stem cells and human cloning has alerted the public (raising its expectations the while) to the possibilities of transferring cell-repair strategies, particularly for neurological diseases, from laboratory to clinic.

    Embryonic stem cells "could prove the Holy Grail in finding treatments for cancer, Parkinson's disease, diabetes, osteoporosis, spinal cord injuries, Alzheimer's disease, leukaemia and multiple sclerosis...transform[ing] the lives of hundreds of thousands of people" (authors' italics; Yvette Cooper, UK Public Health minister, quoted in The Times, Dec 16, 2000). Multiple sclerosis has claimed further newsprint more recently with reports that the first remyelinating-cell implantation into the CNS of a patient with multiple sclerosis has been done ( ).

    How does this extensive lay coverage relate to the true clinical scientific picture? Here we review progress in glial-cell biology, in experimental myelin repair, and in our understanding of the pathology, pathogenesis, and treatment of multiple sclerosis. These advances have established remyelination therapy as a realistic prospect for the current generation of patients with multiple sclerosis.

    Spontaneous myelin repair in multiple sclerosis

    In 1965, ultrastructural studies provided the first clear evidence of spontaneous myelin repair in multiple sclerosis ( figure 1 ), 1 only a few years after the first demonstration of experimental spontaneous CNS remyelination. 2 It has been much studied by contemporary pathologists, 3-6 whose studies offered several interesting historical perspectives. The first was that the classically described "shadow plaque" (Markschattenherde) in fact contains large numbers of uniformly thin myelin sheaths, indicating successful repair of myelin across whole plaques. These shadow plaques are present in acute cases, comprising areas of pale-staining myelin either on the edge of a plaque, or in normal unaffected white matter, and originally were thought to represent a young and active, or incompletely demyelinated, lesion. The second important observation was that Joseph Babinski's often reproduced illustration of myelin phagocytosis in multiple sclerosis also clearly illustrates concurrent myelin repair.


    Figure 1. The first demonstration of spontaneous myelin repair in multiple sclerosis-a substrate upon which all therapeutic remyelinating strategies aim to build. Reproduced with permission of Oxford University Press. 1


    The occurrence of spontaneous remyelination has profound conceptual implications for myelin-repair therapies: no longer is it necessary to create a repair phenomenon de novo; rather, the therapy should stimulate or supplement a spontaneous process. How this might be done depends on understanding of the clinical biology of the disease. The reasons why endogenous repair is not more successful, and whether the limitations can be overcome, can only emerge from a fuller appreciation of the biology of myelinating glial cells.

    Oligodendrocyte progenitor cells
    Quiescent oligodendrocyte progenitor cells (OPC), rather than surviving mature oligodendrocytes, are generally thought to bring about the majority of spontaneous remyelination. 7-10 Large populations of immature oligodendrocytes can be found in fresh lesions, 11,12 including significant numbers of cells with the phenotypic markers of oligodendrocyte precursors. 13-16 Additionally, Schwann cells make a small contribution to endogenous myelin repair, especially in the spinal cord. 6,17,18

    Recent studies have investigated the origin, nature, and limitations of spontaneous myelin repair. That it starts while demyelination is still occurring, as unwittingly shown by Babinski, has been confirmed. 5,19 In the early inflammatory phase of multiple sclerosis some 40% of plaques may contain areas of remyelination occupying 10% or more of plaque volume. 19 This proportion seems to fall as the disease progresses, 20 with the majority of chronic plaques having either no new myelin or a thin peripheral rim.

    Several possible explanations for the ultimate failure of repair have been proposed. First, repeated demyelination appears to impede subsequent repair, 19,21 and the depletion of remyelinating cells is commonly accepted to have a major role. 8,10,22-24 Indeed, oligodendrocyte progenitors may be directly targeted by disease processes. 25 Second, the limited migratory capacity of endogenous progenitors is likely to contribute. 26 Third, molecular changes in chronically demyelinated axons may make them no longer amenable to remyelination. 27 Finally, the progression of the astrocytic scar, obstructing the dispersal of myelin-forming glia within areas of demyelination, also might impede remyelination. 28

    The influence of astrocytes is complex, however. In experimental studies, extensive myelination by implanted cells of oligodendroglial lineage or by Schwann cells occurred unimpeded by host or purified transplanted astrocytes. 29-31 Others have described cohabiting astrocytes and Schwann cells in lesions that show "peripheral" myelin repair. 17,18 Paradoxical roles for astrocytes are increasingly appreciated in oligodendrocyte remyelination: chronic astrocytic scars may obstruct myelin repair by OPC, whereas acutely reactive astrocytes synthesise and release promigratory and proliferative growth factors for OPC.

    Supplementation of remyelination by glial-cell transplantation

    Cells of the oligodendrocyte lineage
    Oligodendrocytes were first discovered only 80 years ago by del Rio Hortega; he also described their principal function, the synthesis of myelin in the CNS. We now know that they develop from a progenitor cell, the properties of which have been much studied since culture techniques offered new opportunities for cell biological investigations. 32,33 Few cell types have been so intensively studied; the growth factors that lead to the proliferation, survival, differentiation, and maturation of oligodendrocyte-lineage cells have been minutely defined.

    Much experimental work on remyelination has focused on the oligodendrocyte lineage. There is an inherent logic in concentrating on these cells. They are the cells lost in multiple sclerosis; it is their normal function to myelinate the CNS, and spontaneous oligodendrocyte remyelination in multiple sclerosis bears witness to their substantial inherent capacity for remyelinating damaged areas of the brain. In addition, there is a wealth of experimental evidence to demonstrate the production of new myelin in animals after transplantation of purified oligodendrocyte-lineage cells 24,34-39 or cell lines. 36,40,41 There is also evidence to suggest that this process is accompanied by both improved conduction 42 and demonstrable functional recovery. 43

    The stage within the oligodendrocyte lineage most suitable for transplantation is important. Although some studies have suggested that mature differentiated oligodendrocytes are useful myelinating cells, 34 others suggest they have only limited capacity. 29,44 Comparative experiments have shown better myelin formation by implanted immature progenitors than mature oligodendrocytes. 37 The majority view is that mitotic potential is an important prerequisite for successful myelin formation, 45 and that postmitotic oligodendrocytes do not readily recapitulate their development to form mature myelin sheaths again.

    A further significant advantage of the progenitor phenotype is a demonstrable migratory potential. 37,46,47 These cells seem to migrate better through demyelinated lesions than do their mature counterparts, which manifest a more complex morphology both in vitro and in vivo. However, endogenous progenitors migrate only 1-2 mm to repopulate demyelinated areas, 26 reflecting a very limited migratory potential through normal brain parenchyma. Astrocytes significantly impede progenitor migration in vitro, 48 as do mature oligodendrocytes, 49 suggesting significant inhibition by surface molecules.

    Transplantation studies also show poor survival and migration when progenitors are implanted into normal white matter, although they are able to populate and remyelinate when injected into, or very close to, lesioned tissue. 50 By contrast, these cells survive well in X-irradiated tissue, which depletes endogenous progenitor numbers. 51 Part of this better survival may reflect competition between endogenous and implanted cells for survival factors, since progenitor numbers increase with increased availability of platelet-derived growth factor 52 or glial growth factor 2. 53 The possibility of improving graft survival and proliferation by the use of growth factors has been explored with some success in vivo. 54

    Investigations of human CNS glia have consistently shown significant biological differences from rodent cells, so that data on rodent OPC cannot be directly extrapolated to human glia. Early studies identified glia similar to the rodent OPC in cultures derived from the fetal human CNS. 55 After transplantation, these cells can synthesise myelin in the dysmyelinated rodent CNS, even after cryopreservation. 56

    More recently, a progenitor was identified in cultures of adult human brain ( figure 2 ) and shown to have similar immunophenotype and differentiation potential to its rodent counterpart. 57-59 But the response to growth factors seemed different-indeed no soluble mitogens for this stage of development have yet been defined. Furthermore, when mixed human oligodendrocyte-lineage cells containing small numbers of these cells were transplanted into demyelinated rat spinal cord, myelin membranes, but not compact multilamellar myelin sheaths, were observed. 60 Methods for selection of these cells (for experimental purposes) from samples of human white matter have since been perfected, 61 but as yet no reports of useful myelin formation after transplantation of adult human progenitors have been published.


    Figure 2. Proliferating adult human oligodendrocyte progenitors, stained with the progenitor marker A2B5 (red), and counterstained for nuclear uptake of BrDU (yellow). Mature oligodendrocytes (stained for galactocerebroside) are stained green.


    Further studies showed that progenitors are identifiable in situ by use of wet-mount tissue print preparations, 62 and more conventional immunohistological techniques have confirmed their presence in normal adult white matter and also in acute and chronic lesions from patients dying with multiple sclerosis ( figure 3 ). 13,15,16 Using the marker NG2, much larger numbers of these cells have recently been identified, 14 although we have not found NG2 to be a specific glial-cell marker. 63,64


    Figure 3. Adult human progenitors grown in cell culture and stained with the monoclonal antibody O4 can exhibit a multi-processed morphology (left); a similar morphology is seen when progenitors in normal adult white matter are stained with antibodies against the platelet-derived growth factor receptor (right).


    In the absence of defined proliferative signals, acquisition of adequate numbers of OPC for therapeutic purposes, whether autologous or heterologous, adult or fetal, remains a problem, and the elucidation of human glial progenitor mitogens (or, perhaps, factors that prevent the proliferation of human progenitors in response to rat OPC mitogens) is emphatically a research priority in assessing their potential for transplantation purposes.

    Schwann cells
    As mentioned above, oligodendrocytes are not the only glial cells that can remyelinate CNS axons; inwardly migrating Schwann cells carry out a proportion of spontaneous myelin repair in multiple sclerosis. A reasonable presumption is that, by contrast with oligodendrocyte-established new myelin, Schwann cells and their myelin sheaths should be resistant to continuing disease-related immunological attack, because little or no peripheral nerve damage occurs in multiple sclerosis. Experimental methods for preparing cultures of adult human Schwann cells from peripheral nerve biopsy samples are now well established. 65,66 These cultures can be purified and expanded in vitro to generate large populations of human Schwann cells. 67

    Perhaps surprisingly, the demonstration that implanted dissociated Schwann cells could remyelinate the rodent CNS preceded comparable oligodendrocyte studies, 39,68 and restoration of normal central conduction to the demyelinated rodent spinal cord by both endogenous 69 and exogenous (transplanted) Schwann cells has been demonstrated. 70 Human Schwann cells successfully lay down new myelin in the spinal cord of mice 71 and rats. The reparative capacity of purified, heregulin-expanded human Schwann cells is not compromised by long-term frozen storage. 67,72 Schwann cells were used in the few patients with multiple sclerosis so far transplanted in a phase I experimental clinical trial ( ).

    Harvesting of autologous Schwann cells from peripheral-nerve biopsy samples, expansion in vitro, and transplantation in patients with multiple sclerosis offers the attractions of ready availability and the avoidance of rejection. Firm evidence is required, however, that expanded human Schwann cells do not form tumours in vivo, a hazard described after transplantation of rodent Schwann cells immortalised by growth factor expansion; 73 unpurified preparations of human peripheral nerve cells result in substantial fibroblast overgrowth with axon destruction. 67 This process presents an imposing barrier to the clinical application of Schwann-cell transplants.

    Another potential problem for the use of Schwann cells in remyelination therapy is the apparent inhibitory effect of astrocytes on Schwann-cell-mediated CNS remyelination, 74-76 though, as mentioned above, the interactions between astrocytes and myelinating glia are complex, suggesting that further research is necessary before the potential for use of Schwann cells in CNS remyelination therapy can be fully assessed.

    Olfactory glia
    Olfactory ensheathing cells (OEC) are found in the olfactory bulb, nerves, and epithelium. They ensheath the axons emanating from olfactory epithelial neurons that penetrate the olfactory bulb of the CNS. Normally, OEC are non-myelinating, but rodent OEC assume a myelinating phenotype similar to that of Schwann cells when transplanted into lesions containing demyelinated axons. 77,78 The ability of OEC to promote CNS axon regeneration and ensheath and myelinate demyelinated axons has led to much interest in the potential of olfactory glia in the field of CNS repair. 79

    One of the potential advantages of OEC over Schwann cells relates to their relationship with astrocytes. In health, OEC coexist alongside astrocytes within the olfactory bulb, whereas in experimentally demyelinated lesions OEC can (by contrast with Schwann cells) ensheath and myelinate axons unimpeded by the astrocytic environment. 77 Rodent OEC migrate far more successfully over astrocytes than Schwann cells in vitro. 80 Human OEC ( figure 4 ), like rodent OEC, are capable of remyelination after transplantation into demyelinated lesions in the rodent spinal cord. 81,82


    Figure 4. Adult human olfactory glia are readily grown in cell culture, and may be an important candidate for implantation in multiple sclerosis.


    Immortalised cell lines
    One possible solution to the problem of obtaining sufficient numbers of cells for transplantation is to use immortalised cell lines, which could yield large numbers of appropriate cells in homogeneity. These cells lines have already proved invaluable in probing the complexity of myelin formation. Much of the work on rodent progenitors has used spontaneously arising lines such as CG4, which retains many of the characteristics of rodent progenitors-including the capacity for spontaneous differentiation and myelination in vivo-but which proliferates indefinitely in vitro under the influence of mitogens. 83 Some human glial cell lines have also been described, mainly derived from tumours, but they have not proved entirely faithful to their primary cell.

    However, the techniques of gene transfer have enabled cell lines to be engineered from primary cells, sometimes by methods in which oncogene activity can be controlled. Conditionally immortalised neonatal rodent progenitors generated in this way repair myelin after transplantation, 36,40,77 although only a proportion of transplanted cells appear to differentiate into terminal, myelinating oligodendrocytes, and some immortalised progenitors may continue to proliferate in vivo in an uncontrolled fashion. Attempts have been made to immortalise human OPC, but evidence of myelin formation in vivo is lacking.

    Despite increasingly elegant and elaborate techniques to prevent malignant transformation, the axiomatic impairment of cellular growth regulation that accompanies the formation of cell lines still carries a significant risk of tumour formation, and this possibility will continue to represent a serious anxiety over the clinical use of implanted immortalised cell lines.

    Xenogeneic transplantation
    An almost limitless source of glial cells for transplantation could potentially be available by xenogeneic transplantation. Many successful remyelination studies in various laboratories prove the feasibility of xenogeneic glial-cell transplantation. 84-86 One disadvantage, however, is the need for more potent immunosuppressive agents such as cyclophosphamide or ciclosporin to prevent tissue rejection; recent studies indicate that drugs such as cyclophosphamide may significantly inhibit remyelination, 87 but ciclosporin is toxic to oligodendrocytes in vitro, inducing apoptosis. 88 The development and availability of genetically engineered pigs designed to escape human rejection 89 could bypass this difficulty, but fears of retroviral or other host infection, much publicised in the UK, will properly delay clinical experimental trials-although patients (for example, with Parkinson's disease) have received porcine xenografts in the USA. 90

    Stem cells
    Rodent embryonic stem cells have substantial remyelinating potential, 91 but their equivalent human sources-aborted fetuses or embryos surplus to requirements from in vitro fertilisation-are not easy to access. Some researchers suggest that stem cells from embryos cloned for the purpose (by cell nuclear transfer) from each patient needing an implant, as recently uniquely legalised in the UK, would have the huge advantage of avoiding rejection. However, the proposal that every patient requiring a transplant would first have to be cloned seems quite unrealistic, and the serious ethical and practical difficulties pertaining to all sources of human embryonic stem cells have stimulated the largely successful search for other sources. 92 It is now clear that neural stem cells are present in the adult rodent brain; 93 large numbers of oligodendrocyte-lineage cells can be generated by neurosphere/oligosphere techniques, 94-96 and these, on transplantation, successfully remyelinate axons. 97 Neural stem cells are also present in the adult human brain ( figure 5 ). 98


    Figure 5. A growing sphere of human neural cells cultured from a temporal lobectomy specimen in our laboratories. Cells are expanded under the influence of growth factors; both neuronal and glial progeny can be generated in this way (diameter of sphere 50 mm).


    Stem cells are also found in adult mammalian skin and in adipose tissue. Importantly, from a therapeutic perspective, adult bone-marrow-derived stem cells 99 also have clear neural potential ( figure 6 ). 100-103 Direct implantation of rodent bone-marrow cells can achieve successful remyelination in the rodent spinal cord. 104 Although it is a little early to predict how successfully the use of stem cells derived from adult human bone marrow will develop, the difficulties in relation to the primary glial cell types may well result in bone-marrow-derived cells becoming the main source of implantable remyelinating cells.


    Figure 6. Adult human mesenchymal stem cells. The cells shown are second passage mesenchymal stem cells (MSC) cultured from normal adult human femoral shaft marrow. Reproduced with permission of Jill Hows, University of Bristol, UK.


    Promotion of endogenous remyelination
    The difficulties of obtaining usable cells and, given the disseminated nature of multiple sclerosis, of knowing where to implant them, increase the attraction of systemic therapies that might have a general effect of promoting endogenous repair.

    In an extensive series of studies, the possibility that immunoglobulins might promote remyelination has been systematically explored. In animals with CNS demyelination caused by chronic Theiler's virus infection, myelin repair was increased by treatment with systemic whole antiserum or purified IgG directed against spinal-cord homogenate. 105 Polyclonal immunoglobulins against myelin basic protein also achieved this effect, as did a monoclonal antibody directed against an oligodendrocyte surface antigen. 106 The antibody belongs to the class of "natural autoantibodies"-naturally occurring polyreactive antibodies of uncertain function and significance. 107 Antibody binding to oligodendrocytes might directly stimulate myelinating function, but in vitro observations suggested that immunoglobulins have no direct effect on oligodendrocyte function. 108 A more likely possibility is that the immunomodulatory and anti-inflammatory consequences of immunoglobulin treatment encourage remyelination. 107,109-111 Furthermore, the first trials of intravenous immunoglobulin as a putative systemic remyelination therapy have now been completed, unfortunately with negative results. 112,113

    Growth-factor treatment to promote remyelination has superficial attractions, but several factors mitigate against this approach: the complex requirements for multiple and different factors during the sequential phases of OPC proliferation, migration, differentiation, and myelination; 114-116 the clear but as yet incompletely explored differences in growth-factor requirements between human and rat OPC; and the fatal effects of the exposure of postmitotic oligodendrocytes to potentially mitogenic growth factors. 117-119 The first trial of systemically delivered insulin-like growth factor 1 in multiple sclerosis has recently been stopped early, and attention is increasingly turning towards glial-cell transplantation as a more promising therapeutic approach.

    Application of experimental remyelination biology to patients with multiple sclerosis

    Site of implantation
    Most experimental studies have explored the effects of transplantation into a single site, but in multiple sclerosis almost innumerable areas of demyelination are commonly disseminated through the CNS ( figure 7 ). Clearly, the prospect of many inoculations into widely disparate lesions is unrealistic. What should not be overlooked, however, is that many plaques are clinically silent, whereas a disproportionate degree of disability emanates from a few critical lesions in eloquent areas in many cases. Thus, implantation into a very small number of carefully selected lesions-for example, the optic nerves, the spinal cord, or the superior cerebellar peduncle-could yield a useful therapeutic dividend. 120 Early phase II clinical trials are likely to proceed on this basis.


    Figure 7. The wide dissemination of lesions throughout the brain and spinal cord emphasises the enormity of the problem, and the need for a highly targeted or focused approach to any implantation strategy. Reproduced from Charcot JM. Lecons sur les Maladies du Systeme Nerveux faites a la Salpetriere, 1872.


    Others continue to pursue a more global myelin-repair strategy, both for multiple sclerosis and for the significantly rarer group of patients with inherited disorders of myelin metabolism. The latter, characterised by diffuse dysmyelination, would require successful remyelination of large tracts to yield any functional improvement. However, in these patients, unlike those with multiple sclerosis, myelin formation is unlikely to be hampered by astrocytic scarring, and the absence of autoimmune myelin destruction could allow a more stable outcome, notwithstanding the suggested contribution of inflammatory processes to myelin damage in adrenoleucodystrophy. 121 Thus far, other strategies using bone-marrow transplantation, gene therapy, or both appear to offer more promise for certain inherited leucodystrophies. 121,122

    An appealing solution to the problems of cell dispersal would be to encourage transplanted cells to migrate widely, as occurs during development. Migration through mature brain parenchyma is very limited, but promigratory agents have been identified, and supplemention of cellular transplantation with growth-factor infusions, 123 or even cotransplantation with growth-factor-secreting cells, 54 has been tried with limited success. Another approach would be to suppress the expression or function of molecules that inhibit migration. 28,124 Finally, studies in neonatal dysmyelinating rodents have shown substantial cell dissemination after intraventricular transplantation, 125 especially after two implantations separated by a few days. 126

    The timing of implantation
    The aim of a remyelinating therapy in patients with multiple sclerosis is to restore function-to reverse certain types of persistent disability, at least partially. The increasingly recognised importance of axonal loss ( figure 8 ) as a pathophysiological substrate of accumulating disability by no means excludes a significant or substantial contribution by persistent demyelination to chronic disability. 127,128 The relative preservation of axons in chronic lesions offers pathological reasons for believing remyelination to have a prospect of functional value, and the transient deterioration in acute and chronic symptoms with fever-Uthoff's phenomenon-provides strong pathophysiological evidence for demyelination as an important substrate for impaired function.


    Figure 8. Axon damage in multiple sclerosis, illustrated here by Greenfield and King (Brain 1936; 59: 445-59). This shows why myelin-repair strategies are unlikely to succeed if initiated too late, while early, succesful repair may help prevent such axon loss. Reproduced with permission of Oxford University Press.


    The timing of a remyelinating treatment in multiple sclerosis, therefore, remains difficult. Clinically, the unpredictable course increases the temptation to defer a potentially hazardous intervention until progressive disability is established and hope of spontaneous recovery extinguished-the first principle in any new therapeutic endeavour must always remain "first, do no harm". From a biological perspective, however, early intervention may offer significant advantages: as mentioned above, this is when spontaneous remyelination occurs, suggesting the most propitious environment, and whatever the specific reasons for failed endogenous repair, most of the explanations offered relate to chronicity. Furthermore, the contribution of progressive axonal loss to secondary progressive multiple sclerosis 128,129 also mitigates against very late intervention; little can be expected of repair strategies when the axonal framework for remyelination has been lost.

    However, axonal loss may paradoxically provide another potent reason for early remyelinating intervention-namely, that progressive axonal damage might be a consequence of persistent myelin loss. 128,130 Axon loss is unlikely to have a single cause. Inflammatory processes almost certainly contribute, perhaps particularly to acute axonal fragmentation, 128,131,132 a feature of acute inflammatory demyelinating lesions. This feature is, however, rather less likely to have pathophysiological effects; the reversible nature of acute relapses is more easily explained by the resolution of oedema and inflammation and by spontaneous remyelination than by axon fragmentation. 128,130 More securely established is the clinical effect of accumulating axon loss in secondary progressive disease, the course of which seems not to be closely influenced by early inflammatory disease activity 133-135 or, sadly, by even the most profound immunosuppressant or anti-inflammatory treatments.

    Such progressive axon fallout may be a late corollary of demyelination. Pathological studies have indicated that axon loss does not correlate with inflammatory cell infiltrate, expression of tumour necrosis factor or nitric oxide, or demyelinating activity, but it is related to the overall extent of established myelin loss. 133,135 Axon loss is seen in lesions that are demyelinated but show little or no inflammation, but it is rare in remyelinated lesions. 135 Demyelination-induced axon loss might occur by several possible mechanisms: directly, through the loss of oligodendrocyte-derived trophic support 136 or axon dependence on myelin sheaths; 137 as a consequence of sustained demyelination-induced conduction block and electrical silence; 138 or indirectly through increased vulnerability of the exposed axon to injurious agents. 139

    Thus, the earlier the intervention, the greater the potential gain. But the significant obstacle to this approach is the risk of losing repaired areas, and carefully prepared and implanted remyelinating cells, to continuing disease activity. Although advances in immunotherapy feed a cautious optimism, no current therapies are able to stop myelin destruction. Concurrent use of potent immunosuppressive agents, perhaps required in any case to prevent graft rejection, might help, yet there is evidence that some of these agents themselves, 87 or the suppression of inflammation in general, 140 may impair myelin regeneration.

    Post-therapy management
    Attention needs to be focused on both clinical management and monitoring after transplantation. Three modes of treatment could be required: continually exogenous trophic support of grafted cells; immunosuppression to prevent graft rejection; and adequate control of disease activity to reduce graft loss. These issues cannot be fully addressed before the early clinical trials, not least because of the substantial differences between animal models and human beings.

    Little information is available for the first issue-continuing exogenous trophic support of grafted cells-though some animal studies do illustrate a potential effect. 54 The adverse influence of antimitotic immunosuppressants on remyelination has been mentioned already. Ciclosporin has been successfully used in Parkinson's disease transplant trials. In relation to multiple sclerosis, antirejection prophylaxis might help inhibit disease progression. The antileucocyte humanised monoclonal antibody Campath-1H, currently under investigation for the treatment of both (solid-organ) transplant rejection and multiple sclerosis 141,142 is particularly promising in this respect. Nevertheless, if cell implantation is adopted, there may be a risk, despite immunosuppression, of inciting new antioligodendrocyte immune reactions that not only see off the graft, but also augment underlying disease processes. Autografting might avoid this outcome.

    Sensitive and precise methods of monitoring graft survival, migration, efficacy of remyelination, and early detection of uncontrolled growth will be essential if these therapeutic protocols are to be explored responsibly in a clinical setting. Furthermore, myelin repair without clinical improvement will be a hollow victory, so robust and reproducible methods of clinical assessment would need to be applied from the start.

    Non-invasive imaging is clearly attractive, most obviously magnetic resonance imaging (MRI) since it is widely available, safe, and well tolerated. Resolution is high, but contrast and specificity are more problematic. Standard protocols cannot disclose remyelination, but advances continue to offer new techniques, of which magnetisation transfer contrast is the strongest candidate for imaging remyelination. 143 Measurement of N-acetyl aspartate levels by magnetic resonance spectroscopy offers the means of assessing any impact on local neuron/axon survival. 144,145

    Use of paramagnetic particles to label cells before transplantation, enabling their dispersion to be tracked by MRI, 146-148 has promise, though from a safety perspective even the most trivial manipulation of cells before implantation would be better avoided. Furthermore, graft survival cannot be inferred from migration, since cells which subsequently die remain visible, 146 and this method not only fails to show new myelin formation but may also impair the ability of other magnetic resonance modalities to do so. Positron emission tomography, although expensive and of limited availability, can be both sensitive and specific, but no appropriate ligands are yet available for monitoring remyelination.

    Serial neurophysiology may also prove to be valuable, and by monitoring conduction times may provide evidence of returning saltatory conduction in the targeted pathways. The optic nerve has particular advantages in this respect.

    If the sites mentioned above-the optic nerve, spinal cord, or brainstem-are selected for the first experimental trials seeking clinical benefit, programmes for rigorous monitoring of both the biological and clinical effects of the intervention need to be established, including not only imaging and electrophysiological examination but also physical assessment of any clinically relevant effects. Specific clinical outcome measures of function, disability, and handicap must be adopted and tailored for each group of patients. Ultimately, success will need to be measured by properly designed clinical trials, in which clinical outcomes are likely to carry the greatest weight. Advances in clinical scale design have improved physical and functional measurement in multiple sclerosis, 149 so that the tools for assessment of clinical outcome, on which remyelination therapies must stand or fall, are becoming available.


    Continued progress in our understanding of the clinical biology of remyelination and of myelinating glia have significantly improved the prospects for cell-implantation therapy to promote remyelination in patients with multiple sclerosis and other diseases characterised by myelin loss. Indeed, clinical experiments have started at Yale University, USA, exploring the effects of cerebral implantation of autologous Schwann cells in patients with multiple sclerosis ( ). In these studies, patients who have received implants will undergo surgical biopsy to assess the effects of implantation after about 6 months.

    The Yale group were also the first to show successful remyelination by bone-marrow-derived stem cells in rodent demyelinating models. Since clinical studies are now being reported of cardiac-muscle repair after direct autologous bone-marrow stem-cell injection in patients with myocardial infarction 150 (the capacity of these cells to differentiate into cardiac myocytes and repair defects having previously been clearly demonstrated in experimental models 151), human mesenchymal stem cells may also be used in patients with multiple sclerosis before long. Other centres are likely to adopt different implantation strategies and may use different sources of glial cells; some will pause until some of the complex hurdles outlined above have been addressed. 152 The next decade will show how successful CNS repair strategies will prove for patients with multiple sclerosis.

    Search strategy and selection criteria

    Data for this review were identified by searches of MEDLINE with the search terms "remyelination" and "myelin repair". Many articles were also identified through searches of the extensive files of the authors. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English were reviewed.

    Authors' contributions

    All authors contributed to all parts of the text: CH made the major contribution to the sections on oligodendrocytes and on clinical application; TB made the major contribution to the Schwann cell and olfactory cell sections; NJS planned, wrote and revised the manuscript.

    Conflict of interest

    None of the authors has a conflict of interest.

    Role of the funding source

    CH is supported by the Multiple Sclerosis Society, and TB by the Wellcome Trust. The Burden Chair Clinical Neurosciences (NS) is supported by the Burden Trust. None of these funding bodies had a role in the preparation of the manuscript.


    1 Perier O, Gregoire A. Electron microscopic features of multiple sclerosis lesions. Brain 1965; 88: 937-52. [PubMed]
    2 Bunge MB, Bunge RP, Ris H. Ultrastructural study of remyelination in an experimental lesion in the adult cat spinal cord. J Biophys Biochem Cytol 1961; 10: 67-94. [PubMed]

    3 Lassmann H, Bruck W, Lucchinetti CF, Rodriguez M. Remyelination in multiple sclerosis. Multiple sclerosis 1997; 3: 133-36. [PubMed]

    4 Prineas JW, Connell F. Remyelination in multiple sclerosis. Ann Neurol 1979; 5: 22-31. [PubMed]

    5 Raine CS, Wu E. Multiple sclerosis: Remyelination in acute lesions. J Neuropathol Exp Neurol 1993; 52: 199-204. [PubMed]

    6 Ludwin S. Remyelination in the central nervous system and in the peripheral nervous system. Adv Neurol 1988; 47: 215-54. [PubMed]

    7 Carroll WM, Jennings AR. Early recruitment of oligodendrocyte precursors in CNS demyelination. Brain 1994; 117: 563-78. [PubMed]

    8 Duncan ID, Grever WE, Zhang SC. Repair of myelin disease: strategies and progress in animal models. Mol Med Today 1997; 3: 554-61. [PubMed]

    9 Wolswijk G. Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 2000; 123: 105-15. [PubMed]

    10 Scolding NJ, Franklin RJM. Remyelination in demyelinating disease. Clinical Neurology. International Practice and Research 1999; 6: 525-48. [PubMed]

    11 Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest 1981; 45: 534-46. [PubMed]

    12 Prineas JW, Kwon EE, Goldenberg PZ. Multiple sclerosis: oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest 1989; 61: 489-503. [PubMed]

    13 Scolding NJ, Franklin RJM, Stevens S, Heldin CH, Compston DAS, Newcombe J. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 1998; 121: 2221-28. [PubMed]

    14 Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 2000; 20: 6404-12. [PubMed]

    15 Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 1998; 18: 601-09. [PubMed]

    16 Maeda Y, Solanky M, Menonna J, Chapin J, Li W, Dowling P. Platelet-derived growth factor-alpha receptor-positive oligodendroglia are frequent in multiple sclerosis lesions. Ann Neurol 2001; 49: 776-85. [PubMed]

    17 Ogata J, Feigin I. Schwann cells and regenerated peripheral myelin in multiple sclerosis: an ultrastructural study. Neurology 1975; 25: 713-16. [PubMed]

    18 Itoyama Y, Webster HD, Richardson-EP J, Trapp BD. Schwann cell remyelination of demyelinated axons in spinal cord multiple sclerosis lesions. Ann Neurol 1983; 14: 339-46. [PubMed]

    19 Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 1993; 33: 137-51. [PubMed]

    20 Ozawa K, Suchanek G, Breitschopf H, et al. Patterns of oligodendroglia pathology in multiple sclerosis. Brain 1994; 117: 1311-22. [PubMed]

    21 Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer L, Cho ES. Multiple sclerosis: pathology of recurrent lesions. Brain 1993; 116: 681-93. [PubMed]

    22 Kierstead HS, Blakemore WF. Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia 1997; 22: 161-70. [PubMed]

    23 Carroll WM, Jennings AR, Ironside LJ. Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination. Brain 1998; 121: 293-302. [PubMed]

    24 Rosenbluth J. Glial transplantation in the treatment of myelin loss or deficiency. In: Bostock H. , Kirkwood P.A. , Pullen A.H. (Eds.) 1996; The neurobiology of disease: contributions from neuroscience to clincial neurology pp. 124-48. Cambridge: Cambridge University Press

    25 Niehaus A, Shi J, Grzenkowski M, et al. Patients with active relapsing-remitting multiple sclerosis synthesize antibodies recognizing oligodendrocyte progenitor cell surface protein: implications for remyelination. Ann Neurol 2000; 48: 362-71. [PubMed]

    26 Franklin RJ, Gilson JM, Blakemore WF. Local recruitment of remyelinating cells in the repair of demyelination in the central nervous system. J Neurosci Res 1997; 50: 337-44. [PubMed]

    27 Charles P, Hernandez MP, Stankoff B, et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc Natl Acad Sci USA 2000; 97: 7585-90. [PubMed]

    28 Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Res Bull 1999; 49: 377-91. [PubMed]

    29 Archer DR, Cuddon PA, Lipsitz D, Duncan ID. Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nat Med 1997; 3: 54-59. [PubMed]

    30 Duncan ID, Hoffman RL. Schwann cell invasion of the central nervous system of the myelin mutants. J Anat 1997; 190: 35-49. [PubMed]

    31 Franklin RJ, Crang AJ, Blakemore WF. Transplanted type-1 astrocytes facilitate repair of demyelinating lesions by host oligodendrocytes in adult rat spinal cord. J Neurocytol 1991; 20: 420-30. [PubMed]

    32 Raff MC, Miller RH, Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 1983; 303: 390-96. [PubMed]

    33 Skoff RP. The lineages of neuroglial cells. Neuroscientist 1996; 2: 335-44. [PubMed]

    34 Duncan ID, Paino C, Archer DR, Wood PM. Functional capacities of transplanted cell-sorted adult oligodendrocytes. Dev Neurosci 1992; 14: 114-22. [PubMed]

    35 Franklin RJM, Blakemore WF. Transplanting oligodendrocyte progenitors into the adult CNS. J Anat 1997; 190: 23-33. [PubMed]

    36 Groves AK, Barnett SC, Franklin RJM, et al. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 1993; 362: 453-55. [PubMed]

    37 Warrington AE, Barbarese E, Pfeiffer SE. Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J Neurosci Res 1993; 34: 1-13. [PubMed]

    38 Kocsis JD. Restoration of function by glial cell transplantation into demyelinated spinal cord. J Neurotrauma 1999; 16: 695-703. [PubMed]

    39 Baron-Van Evercooren A, Avellana-Adalid V, Lachapelle F, Liblau R. Schwann cell transplantation and myelin repair of the CNS. Mult Scler 1997; 3: 157-61. [PubMed]

    40 Barnett SC, Franklin RJM, Blakemore WF. In vitro and in vivo analysis of a rat bipotential O-2A progenitor cell line containing the temperature-sensitive mutant gene of the SV40 large T antigen. Eur J Neurosci 1993; 5: 1247-60. [PubMed]

    41 Tontsch U, Archer DR, DuboisDalcq M, Duncan ID. Transplantation of an oligodendrocyte cell line leading to extensive myelination. Proc Natl Acad Sci USA 1994; 91: 11616-20. [PubMed]

    42 Utzschneider DA, Archer DR, Kocsis JD, Waxman SG, Duncan ID. Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin- deficient rat. Proc Natl Acad Sci USA 1994; 91: 53-57. [PubMed]

    43 Jeffery ND, Crang AJ, O'Leary MT, Hodge SJ, Blakemore WF. Behavioural consequences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord. Eur J Neurosci 1999; 11: 1508-14. [PubMed]

    44 Kierstead HS, Blakemore WF. Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J Neuropathol Exp Neurol 1997; 56: 1191-01. [PubMed]

    45 Blakemore WF, Keirstead HS. The origin of remyelinating cells in the central nervous system. J Neuroimmunol 1999; 98: 69-76. [PubMed]

    46 Baron van Evercooren A, Avellana Adalid V, BenYounes Chennoufi A, Gansmuller A, NaitOumesmar B, Vignais L. Cell-cell interactions during the migration of myelin-forming cells transplanetd in the demyelinated spinal cord. Glia 1996; 16: 147-64. [PubMed]

    47 Kiernan BW, Ffrench-Constant C. Oligodendrocyte precursor (O-2A progenitor cell) migration; a model system for the study of cell migration in the developing central nervous system. Dev suppl 1993; 219-225.

    48 Fok-Seang J, Mathews GA, Ffrench-Constant C, Trotter J, Fawcett JW. Migration of oligodendrocyte precursors on astrocytes and meningeal cells. Dev Biol 1995; 171: 1-15. [PubMed]

    49 Jefferson S, Jacques T, Kiernan BW, Scott-Drew S, Milner R, Ffrench-Constant C. Inhibition of oligodendrocyte precursor motility by oligodendrocyte processes: implications for transplantation-based approaches to multiple sclerosis. Mult Scler 1997; 3: 162-67. [PubMed]

    50 Franklin RJM, Bayley SA, Blakemore WF. Transplanted CG4 cells (an oligodendrocyte progenitor cell line) survive, migrate, and contribute to repair of areas of demyelination in X-irradiated and damaged spinal cord but not in normal spinal cord. Exp Neurol 1996; 137: 263-76. [PubMed]

    51 Hinks GL, Chari DM, O'Leary MT, et al. Depletion of endogenous oligodendrocyte progenitors rather than increased availability of survival factors is a likely explanation for enhanced survival of transplanted oligodendrocyte progenitors in X-irradiated compared to normal CNS. Neuropathol Appl Neurobiol 2001; 27: 59-67. [PubMed]

    52 Barres BA, Hart IK, Coles HS, et al. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 1992; 70: 31-46. [PubMed]

    53 Noel F, Raju U, Happel E, Marchionni MA, Tofilon PJ. X-irradiation-induced loss of O-2A progenitor cells in rat spinal cord is inhibited by implants of cells engineered to secrete glial growth factor 2. Neuroreport 1999; 10: 535-40. [PubMed]

    54 Milward EA, Zhang SC, Zhao M, et al. Enhanced proliferation and directed migration of oligodendroglial progenitors co-grafted with growth factor-secreting cells. Glia 2000; 32: 264-70. [PubMed]

    55 Kennedy PGE, FokSeang J. Studies on the development, antigenic phenotype and function of human glial cells in tissue culture. Brain 1986; 109: 1261-77. [PubMed]

    56 Seilhean D, Gansmuller A, Baronvan Evercooren A, Gumpel M, Lachapelle F. Myelination by transplanted human and mouse central nervous system tissue after long-term cryopreservation. Acta Neuropathol 1996; 91: 82-88. [PubMed]

    57 Prabhakar S, D'Souza S, Antel JP, McClaurin JA, Schipper HM, Wang E. Phenotypic and cell-cycle properties of human oligodendrocytes in vitro. Brain Res 1995; 672: 159-69. [PubMed]

    58 Armstrong RC, Dorn HH, Kufta CV, Friedman E, DuboisDalcq ME. Pre-oligodendrocytes from adult human CNS. J Neurosci 1992; 12: 1538-47. [PubMed]

    59 Scolding NJ, Rayner PJ, Sussman J, Shaw C, Compston DAS. A proliferative adult human oligodendrocyte progenitor. Neuroreport 1995; 6: 441-45. [PubMed]

    60 Targett MP, Sussman J, Scolding N, O'Leary MT, Compston DAS, Blakemore WF. Failure to achieve remyelination of demyelinated rat axons following transplantation of glial cells obtained from the adult human brain. Neuropathol Appl Neurobiol 1996; 22: 199-206. [PubMed]

    61 Roy NS, Wang S, Harrison-Restelli C, et al. Identification, isolation, and promoter-defined separation of mitotic oligodendrocyte progenitor cells from the adult human subcortical white matter. J Neurosci 1999; 19: 9986-95. [PubMed]

    62 Scolding NJ, Rayner PJ, Compston DA. Identification of A2B5-positive putative oligodendrocyte progenitor cells and A2B5-positive astrocytes in adult human white matter. Neuroscience 1999; 89: 1-4. [PubMed]

    63 Pouly S, Becher B, Blain M, Antel JP. Expression of a homologue of rat NG2 on human microglia. Glia 1999; 27: 259-68. [PubMed]

    64 Pouly S, Prat A, Blain M, Olivier A, Antel J. NG2 immunoreactivity on human brain endothelial cells. Acta Neuropathol 2001; 102: 313-20. [PubMed]

    65 Morrissey TK, Levi AD, Nuijens A, Sliwkowski MX, Bunge RP. Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc Natl Acad Sci USA 1995; 92: 1431-35. [PubMed]

    66 Rutkowski JL, Kirk CJ, Lerner MA, Tennekoon GI. Purification and expansion of human Schwann cells in vitro. Nat Med 1995; 1: 80-83. [PubMed]

    67 Brierley CM, Crang AJ, Iwashita Y, et al. Remyelination of demyelinated CNS axons by transplanted human schwann cells: the deleterious effect of contaminating fibroblasts. Cell Transplant 2001; 10: 305-15. [PubMed]

    68 Harrison BM. Remyelination by cells introduced into a stable demyelinating lesion in the central nervous system. J Neurol Sci 1980; 46: 63-81. [PubMed]

    69 Felts PA, Smith KJ. Conduction properties of central nerve fibers remyelinated by Schwann cells. Brain Res 1992; 574: 178-92. [PubMed]

    70 Honmou O, Felts PA, Waxman SG, Kocsis JD. Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. J Neurosci 1996; 16: 3199-208. [PubMed]

    71 Levi ADO, Bunge RP. Studies of myelin formation after transplantation of human Schwann cells into the severe combined immunodeficient mouse. Exp Neurol 1994; 130: 41-52. [PubMed]

    72 Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci 2001; 21: 944-50. [PubMed]

    73 Langford LA, Porter S, Bunge RP. Immortalized rat Schwann cells produce tumours in vivo. J Neurocytol 1988; 17: 521-29. [PubMed]

    74 Franklin RJM, Blakemore WF. Requirements for Schwann cell migration within CNS environments: a viewpoint. Int J Dev Neurosci 1993; 11: 641-49. [PubMed]

    75 Harrison B. Schwann cell and oligodendrocyte remyelination in lysolecithin-induced lesions in irradiated rat spinal cord. J Neurol Sci 1985; 67: 143-59. [PubMed]

    76 Woodruff RH, Franklin RJ. Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study. Glia 1999; 25: 216-28. [PubMed]

    77 Franklin RJM, Gilson JM, Franceschini IA, Barnett SC. Schwann cell-like myelination following transplantation of an olfactory bulb-ensheathing cell-line into areas of demyelination in the adult CNS. Glia 1996; 17: 217-24. [PubMed]

    78 Imaizumi T, Lankford KL, Waxman SG, Greer CA, Kocsis JD. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J Neurosci 1998; 18: 6176-85. [PubMed]

    79 Franklin RJ, Barnett SC. Olfactory ensheathing cells and CNS regeneration: the sweet smell of success?. Neuron 2000; 28: 15-18. [PubMed]

    80 Lakatos A, Franklin RJ, Barnett SC. Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes. Glia 2000; 32: 214-25. [PubMed]

    81 Barnett SC, Alexander CL, Iwashita Y, et al. Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 2000; 123: 1581-88. [PubMed]

    82 Kato T, Honmou O, Uede T, Hashi K, Kocsis JD. Transplantation of human olfactory ensheathing cells elicits remyelination of demyelinated rat spinal cord. Glia 2000; 30: 209-18. [PubMed]

    83 Louis JC, Magal E, Muir D, Manthorpe M, Varon S. CG-4, a new bipotential glial cell line from rat brain, is capable of differentiating in vitro into either mature oligodendrocytes or type-2 astrocytes. J Neurosci Res 1992; 31: 193-204. [PubMed]

    84 Archer DR, Leven S, Duncan ID. Myelination by cryopreserved xenografts and allografts in the myelin- deficient rat. Exp Neurol 1994; 125: 268-77. [PubMed]

    85 Crang AJ, Blakemore WF. Remyelination of demyelinated rat axons by transplanted mouse oligodendrocytes. Glia 1991; 4: 305-13. [PubMed]

    86 Rosenbluth J, Liu Z, Guo D, Schiff R. Myelin formation by mouse glia in myelin-deficient rats treated with cyclosporine. J Neurocytol 1993; 22: 967-77. [PubMed]

    87 Smith PM, Franklin RJ. The effect of immunosuppressive protocols on spontaneous CNS remyelination following toxin-induced demyelination. J Neuroimmunol 2001; 119: 261-68. [PubMed]

    88 McDonald JW, Goldberg MP, Gwag BJ, Chi SI, Choi DW. Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures. Ann Neurol 1996; 40: 750-58. [PubMed]

    89 Edge AS, Gosse ME, Dinsmore J. Xenogeneic cell therapy: current progress and future developments in porcine cell transplantation. Cell Transplant 1998; 7: 525-39. [PubMed]

    90 Deacon T, Schumacher J, Dinsmore J, et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nat Med 1997; 3: 350-53. [PubMed]

    91 Brustle O, Jones KN, Learish RD, et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 1999; 285: 754-56. [PubMed]

    92 Scolding N. New cells from old. Lancet 2001; 357: 329-30. [PubMed]

    93 Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 1996; 16: 7599-09. [PubMed]

    94 Rogister B, Ben Hur T, Dubois-Dalcq M. From neural stem cells to myelinating oligodendrocytes. Mol Cell Neurosci 1999; 14: 287-300. [PubMed]

    95 Avellana AV, Nait OB, Lachapelle F, Baron-Van EA. Expansion of rat oligodendrocyte progenitors into proliferative "oligospheres" that retain differentiation potential. J Neurosci Res 1996; 45: 558-70. [PubMed]

    96 Zhang SC, Lipsitz D, Duncan ID. Self-renewing canine oligodendroglial progenitor expanded as oligospheres. J Neurosci Res 1998; 54: 181-90. [PubMed]

    97 Zhang SC, Ge B, Duncan ID. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc Natl Acad Sci USA 1999; 96: 4089-94. [PubMed]

    98 Kukekov VG, Laywell ED, Suslov O, et al. Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol 1999; 156: 333-44. [PubMed]

    99 Colter DC, Sekiya I, Prockop DJ. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci USA 2001; 98: 7841-45. [PubMed]

    100 Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000; 290: 1775-79. [PubMed]

    101 Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61: 364-70. [PubMed]

    102 Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999; 96: 10711-16. [PubMed]

    103 Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000; 290: 1779-82. [PubMed]

    104 Sasaki M, Honmou O, Akiyama Y, Uede T, Hashi K, Kocsis JD. Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia 2001; 35: 26-34. [PubMed]

    105 Rodriguez M, Lennon VA, Benveniste EN, Merrill JE. Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 1987; 46: 84-95. [PubMed]

    106 Asakura K, Miller DJ, Murray K, Bansal R, Pfeiffer SE, Rodriguez M. Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 1996; 43: 273-81. [PubMed]

    107 Miller DJ, Rodriguez M. A monoclonal autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a natural autoantibody encoded by germline immunoglobulin genes. J Immunol 1995; 154: 2460-69. [PubMed]

    108 Stangel M, Compston DAS, Scolding NJ. Polyclonal immunoglobulins for intravenous use do not influence the behaviour of cultured oligodendrocytes. J Neuroimmunol 1999; 96: 228-33. [PubMed]

    109 Miller DJ, Rivera Quinones C, Njenga MK, Leibowitz J, Rodriguez M. Spontaneous CNS remyelination in beta2 microglobulin-deficient mice following virus-induced demyelination. J Neurosci 1995; 15: 8345-52. [PubMed]

    110 Stangel M, Compston A, Scolding NJ. Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ("IVIg"). J Neuroimmunol 2000; 103: 195-201. [PubMed]

    111 Stangel M, Joly E, Scolding NJ, Compston DA. Normal polyclonal immunoglobulins ("IVIg") inhibit microglial phagocytosis in vitro. J Neuroimmunol 2000; 106: 137-44. [PubMed]

    112 Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 68: 89-92. [PubMed]

    113 Noseworthy JH, O'Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000; 55: 1135-43. [PubMed]

    114 Franklin RJ, Hinks GL, Woodruff RH, O'Leary MT. What roles do growth factors play in CNS remyelination?. Prog Brain Res 2001; 132: 185-93. [PubMed]

    115 Hinks GL, Franklin RJ. Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 2000; 16: 542-56. [PubMed]

    116 Hinks GL, Franklin RJ. Distinctive patterns of PDGF-A, FGF-2, IGF-I, and TGF-beta1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Mol Cell Neurosci 1999; 14: 153-68. [PubMed]

    117 Casaccia-Bonnefil P, Carter BD, Dobrowsky RT, Chao MV. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996; 383: 716-19. [PubMed]

    118 Muir DA, Compston DAS. Growth factor stimulation triggers apoptotic cell death in mature oligodendrocytes. J Neurosci Res 1996; 44: 1-11. [PubMed]

    119 Scolding NJ, Compston DA. Growth factors fail to protect rat oligodendrocytes against humoral injury in vitro. Neurosci Lett 1995; 183: 75-78. [PubMed]

    120 Compston DAS. Remyelination of the central nervous system. Mult Scler 1996; 1: 388-92. [PubMed]

    121 Berger J, Moser HW, Forss-Petter S. Leukodystrophies: recent developments in genetics, molecular biology, pathogenesis and treatment. Curr Opin Neurol 2001; 14: 305-12. [PubMed]

    122 Krivit W, Lockman LA, Watkins PA, Hirsch J, Shapiro EG. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 1995; 18: 398-412. [PubMed]

    123 Fricker-Gates RA, Winkler C, Kirik D, Rosenblad C, Carpenter MK, Bjorklund A. EGF Infusion stimulates the proliferation and migration of embryonic progenitor cells transplanted in the adult rat striatum. Exp Neurol 2000; 165: 237-47. [PubMed]

    124 Schnadelbach O, Blaschuk OW, Symonds M, Gour BJ, Doherty P, Fawcett JW. N-cadherin influences migration of oligodendrocytes on astrocyte monolayers. Mol Cell Neurosci 2000; 15: 288-302. [PubMed]

    125 Learish RD, Brustle O, Zhang SC, Duncan ID. Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin. Ann Neurol 1999; 46: 716-22. [PubMed]

    126 Mitome M, Low HP, van Den PA, et al. Towards the reconstruction of central nervous system white matter using neural precursor cells. Brain 2001; 124: 2147-61. [PubMed]

    127 Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci 1999; 354: 1649-73. [PubMed]

    128 Bjartmar C, Trapp BD. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 2001; 14: 271-78. [PubMed]

    129 Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 2000; 48: 893-901. [PubMed]

    130 Scolding N, Franklin R. Axon loss in multiple sclerosis. Lancet 1998; 352: 340-41. [PubMed]

    131 Trapp BD, Peterson J, Ransohoff RM, Rudick RA, Mork S, Bo L. Axon transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278-85. [PubMed]

    132 Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393-99. [PubMed]

    133 Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000; 123: 1174-83. [PubMed]

    134 Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343: 1430-38. [PubMed]

    135 Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000; 157: 267-76. [PubMed]

    136 Meyer Franke A, Kaplan MR, Pfrieger FW, Barres BA. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 1995; 15: 805-19. [PubMed]

    137 Griffiths I, Klugmann M, Anderson T, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 1998; 280: 1610-13. [PubMed]

    138 Lipton SA. Blockade of electrical-activity promotes the death of mammalian retinal ganglion-cells in culture. Proc Natl Acad Sci USA 1986; 83: 9774-78. [PubMed]

    139 Raine CS, Cross AH. Axonal dystrophy as a consequence of long-term demyelination. Lab Invest 1989; 60: 714-25. [PubMed]

    140 Cuzner ML, Loughlin AJ, Mosley K, Woodroofe MN. The role of microglia macrophages in the processes of inflammatory demyelination and remyelination. Neuropathol Appl Neurobiol 1994; 20: 200-01. [PubMed]

    141 Hale G, Waldmann H. Recent results using CAMPATH-1 antibodies to control GVHD and graft rejection. Bone Marrow Transplant 1996; 17: 305-08. [PubMed]

    142 Moreau T, Thorpe J, Miller D, et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994; 344: 298-301. [PubMed]

    143 Deloire-Grassin MS, Brochet B, Quesson B, et al. In vivo evaluation of remyelination in rat brain by magnetization transfer imaging. J Neurol Sci 2000; 178: 10-16. [PubMed]

    144 Davie CA, Barker GJ, Webb S, et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995; 118: 1583-92. [PubMed]

    145 De Stefano N, Matthews PM, Antel JP, Preul M, Francis G, Arnold DL. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol 1995; 38: 901-09. [PubMed]

    146 Bulte JW, Zhang S, van Gelderen P, et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci USA 1999; 96: 15256-61. [PubMed]

    147 Franklin RJ, Blaschuk KL, Bearchell MC, et al. Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain. Neuroreport 1999; 10: 3961-65. [PubMed]

    148 Lewin M, Carlesso N, Tung CH, et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol 2000; 18: 410-14. [PubMed]

    149 Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain 2001; 124: 962-73. [PubMed]

    150 Strauer BE, Brehm M, Zeus T, et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction]. Dtsch Med Wochenschr 2001; 126: 932-38. [PubMed]

    151 Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001; 107: 1395-402. [PubMed]

    152 Scolding N. Regenerating myelin. Brain 2001; 124: 2129-30. [PubMed]


    a, b, c CH, TB, and NS are all at the Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.

    Correspondence: Professor Neil J Scolding, Burden Professor of Clinical Neurosciences, University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UK. Tel +44 (0) 117 970 1212; fax +44 (0) 117 975 3824

  • #2
    Kim, while it is fine to post a long article... you might want to consider attaching the article. The reason is that people have to scroll down a long ways to see responses to the article. Wise.


    • #3