Nature Medicine
8, 1075 - 1076 (2002)
doi:10.1038/nm1002-1075
Myelin failure in multiple sclerosis: Breaking the spell of NotchReinhard HohlfeldInstitute for Clinical Neuroimmunology Ludwig Maximilians University, Munich and Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany hohlfeld@neuro.npg.de In multiple sclerosis, the myelin sheath is heavily damaged. New evidence suggests that inhibitory signals mediated by the Notch pathway suppress remyelination (pages 1115−1121).Loss of myelin, the fatty sheath that envelops most axons, is a hallmark of multiple sclerosis (MS). MS lesions can occur anywhere in the central nervous system (CNS). In most cases, demyelination is mediated by inflammatory cells and their secreted products, but the detailed mechanisms of myelin damage differ in the various types of MS (ref. 1). Axonal loss also occurs in MS, probably as a consequence of demyelination. Apart from oligodendrocytes, which produce the myelin sheath, MS lesions comprise axons and cells that provide neuronal support and protection, that is, astrocytes and microglia. In addition, inflammatory cells contribute to lesion formation by invading the CNS via small blood vessels. There they attack myelin, oligodendrocytes and perhaps axons as well (Fig. 1). In chronic lesions, the lost axons and myelin are replaced by dense, 'sclerotic' astrocytic scar tissue, hence the name multiple sclerosis. Spontaneous remyelination does occur in MS lesions, but in the long term it cannot prevent irreversible axonal damage.
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A study in this issue proposes a new link between the inflammatory milieu and the failure of efficient remyelination2. John et al. suggest that inflammatory cells not only directly damage myelin, but they also create an environment in which surviving oligodendrocyte precursors fail to differentiate and myelinate. The authors report that transforming growth factor- 1 (TGF-1), a cytokine produced by immune as well as other types of cells, stimulates astrocytes to express a surface protein called Jagged1. This protein binds to Notch receptors on the oligodendrocytes, and the receptors mediate signals that, in effect, inhibit the maturation of the oligodendrocytes. This pathway could provide a molecular handle for the therapeutic induction of myelination.
In an elegant series of experiments, the investigators first identified candidate genes that are upregulated in cultured astrocytes after stimulation by the inflammatory cytokines present in MS lesions. Using microarray expression profiling, they found that TGF-1 strongly induced Jagged1 expression, whereas other inflammatory cytokines did not. These results were confirmed on the protein level by western blotting and confocal microscopy. Jagged1 is a ligand for Notch1, a member of the Notch protein family first identified in Drosophila. The Notch proteins are highly conserved transmembrane receptors that decide many crucial questions of cell differentiation and cell fate.
To test if these in vitro observations were relevant to clinical reality, John et al. studied MS lesions by immunohistochemistry. They found Jagged1, its receptor Notch1, and Hes5, a downstream effector of Notch1, in chronic demyelinating MS lesions. In contrast, these proteins were not present in remyelinated lesions. Jagged1 was present in activated astrocytes, whereas Notch1 and Hes5 were found in immature oligodendrocytes. To detect any functional effects that Jagged1 might have on oligodendrocytes, the researchers cultured human oligodendrocytes together with fibroblasts transfected with human Jagged1. In these cocultures, the oligodendrocytes did not extend their processes, a pattern consistent with an immature phenotype.
These data are the first to implicate the Notch pathway in failures of remyelination in MS. They point to a qualitative rather than quantitative defect of oligodendrocyte precursors. Thus the results are consistent with histological studies demonstrating that even chronic MS lesions contain oligodendrocyte precursors, although their prevalence decreases with increasing age of the lesion and patient.3 The new findings together with results from other studies4 indicate that at least three factors are involved in reducing or obstructing remyelination: 1) loss of oligodendrocytes and oligodendrocyte precursors due to immune attack; 2) inhibitory signal(s) from the inflammatory milieu2 and obstruction of oligodendrocytes by astrocytic scarring; and 3) reduced receptiveness of injured axons to remyelination5,
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Clearly, a better understanding of these mechanisms is crucial for designing therapies to improve remyelination. But many questions remain. For one, is it a good strategy to inhibit TGF-1? Probably not, because TGF-1 and other TGF- isoforms have many different effects on different cell types including immune cells7. For example, TGF- can downregulate inflammatory reactions. Indeed, TGF-1 and TGF-2 are beneficial in an animal model of MS, experimental autoimmune encephalomyelitis (EAE)8, and TGF-2 has been tested in a pilot trial in MS patients8. Instead of trying to inhibit TGF-, it might be better to aim at events of the inhibitory cascade further downstream2. Ideally, only the myelin-related function of the Notch pathway should be targeted, as Notch regulates numerous processes in many cell types, including immune cells9. It is currently difficult to speculate on how to do this, but further experiments could reveal clues, such as myelination-specific Notch mediators.
Meanwhile we must remain open to other remyelination strategies (Fig. 2). For example, two papers recently published in Nature Medicine demonstrate that trophic(growth) factors like leukemiainhibitory factor (LIF) and ciliary neuro-trophic factor (CNTF) positively influence myelination in EAE (refs. 10,11). The unsolved problem, is how to apply these proteins to ensure that they effectively reach MS lesions. Certain immunoglobulins with myelination-inducing po- tential12 are already being used for MS, but mainly because of their immunomodulatory properties.
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Another strategy that has attracted attention lately is the transplantation of myelin-forming cells, their precursors or even stem cells in clinically relevant lesions. Such lesions include a spinal cord lesion, causing paralysis, and bilateral optic nerve lesions, causing blindness13. Clinical pilot trials have begun to explore the effects of implanting autologous Schwann cells, the myelin-forming cells of the peripheral nervous system, into MS lesions13.
It would make sense to combine a Notch-based approach based on the new study with growth factor or transplantation therapies, plus an efficient immunomodulatory treatment to protect the remyelinating cells from the ongoing immune attack. First, however, we must identify the unknown agent that can block or cancel the myelination-inhibiting signals sent along the Notch pathway. This promises to be a major challenge, but one well worth the effort.
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