Brain, Vol. 123, No. 1, 105-115,
January 2000
© 2000 Oxford University Press
Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Amsterdam, The Netherlands
Correspondence to:
Guus Wolswijk, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands E-mail: G.Wolswijk{at}nih.knaw.nl
One of the hallmarks of the human demyelinating disease multiple sclerosis is the inability to compensate adequately for the loss of myelin and of oligodendrocytes, the myelin-forming cells of the CNS. Oligodendrocyte precursor cells, a potential source of oligodendrocytes, have been identified in lesions of chronic multiple sclerosis, but it is not known whether they develop into new, fully differentiated oligodendrocytes, capable of remyelination. Sections of post-mortem multiple sclerosis tissue were therefore immunolabelled with antibodies to galactocerebroside (GalC), the first oligodendrocyte-specific molecule to be expressed by differentiating oligodendrocyte precursor cells, and myelin oligodendrocyte glycoprotein (MOG), a marker for mature oligodendrocytes. In total, 23 lesions from 15 subjects with chronic progressive multiple sclerosis were analysed. The immunolabelling revealed that chronic multiple sclerosis lesions contain only small numbers of immature, process-bearing, GalC-positive oligodendrocytes (0–2 cells/mm2 in 10 µm thick sections); they had a relatively large, pale nucleus (maximum diameter: 9.9 ± 0.9 µm). Although they appeared to make contact with surrounding demyelinated axons, most immature oligodendrocytes appeared not to be engaged in myelination. These findings suggest that oligodendrocyte differentiation of precursor cells is a rare event in chronic multiple sclerosis, which is consistent with the general failure of myelin repair during the later stages of this disease. The lesions in the collection, in particular those with recent demyelinating activity, contained another distinct population of oligodendrocytes. It consisted of small, round cells with a small, dense nucleus (maximum diameter: 6.8 ± 0.8 µm) that expressed both GalC and MOG but lacked processes, suggesting that these cells were mature oligodendrocytes that had survived the loss of their myelin sheaths, i.e. they were demyelinated oligodendrocytes. In the most recent lesions in the collection, the demyelinated oligodendrocytes were found in large numbers throughout the centre of the lesion (up to 700 cells/mm2), while in the older lesions they were found only at the edges. Moreover, when the borders of these older lesions still contained numerous macrophages, they tended to contain more demyelinated oligodendrocytes than those lacking macrophages. These findings suggest that mature, demyelinated oligodendrocytes gradually disappear from lesion areas with increasing age of the lesion. The present study thus suggests that the failure of myelin repair in at least some cases of chronic multiple sclerosis is due to (i) the loss of demyelinated oligodendrocytes from lesion areas and (ii) the failure of the oligodendrocyte precursor population to expand and generate new oligodendrocytes. Gaining further insight into these processes may prove crucial for the development of remyelination promoting strategies.
GalC; MOG; multiple sclerosis; oligodendrocyte precursor cell; remyelination
GalC = galactocerebroside; GFAP = glial fibrillary acidic protein; LCA = leucocyte common antigen; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein; mAb = monoclonal antibody; PDGF = platelet-derived growth factor
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