Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells - PubMed (original) (raw)

Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells

G Wolswijk. J Neurosci. 1998.

Abstract

In the past decade, considerable progress has been made in the understanding of the biology of rodent oligodendrocyte precursor cells and their role in the generation of oligodendrocytes in the developing and adult rodent CNS. Much less is known about human oligodendrocyte lineage cells and about the reasons for the failure of the regeneration of the oligodendrocyte population during chronic stages of multiple sclerosis (MS). In particular, the fate of the oligodendrocyte precursor population in MS has remained elusive. The present study examined the possibility that oligodendrocyte regeneration ultimately fails because of the local destruction of both oligodendrocytes and their precursor cells. Analysis of chronic stage MS tissue suggested that this is not the case, because all chronic MS lesions studied contained significant numbers of oligodendrocyte precursor cells, identified as process-bearing cells that bound the O4 antibody but not antibodies to GalC and GFAP. The oligodendrocyte precursor cells appeared, however, to be relatively quiescent, because none expressed the nuclear proliferation antigen recognized by the Ki-67 antibody, and because most lesions lacked myelinating oligodendrocytes in their centers. Thus, it appears that the regeneration of the oligodendrocyte population fails during chronic stages of MS because of the inability of oligodendrocyte precursor cells to proliferate and differentiate rather than because of the local destruction of all oligodendrocyte lineage cells. The identification of ways of stimulating the endogenous oligodendrocyte precursor population to expand and generate remyelinating cells may represent an alternative to transplantation of oligodendrocyte lineage cells to promote myelin repair in MS.

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Figures

Fig. 1.

Fig. 1.

Some characteristics of the chronic MS lesions in the collection. A, B, Variable numbers of neurofilament (NF)-positive axons (A) that were surrounded by MBP-positive myelin segments (arrowheads) (B) were observed in the center of three of the chronic lesions. Detail of lesion R, subject 97-006. C, Numerous GalC-positive oligodendrocytes lacking processes were present in four of the chronic MS lesions analyzed. Such rounded oligodendrocytes were also present in the borders of the lesions with an oligodendrocyte-free center. Detail of lesion H, subject 96-040. D, Many of the chronic MS lesions contained debris-laden macrophages, which were easily identifiable when sections were examined under phase-contrast optics; this semi-phase contrast image was generated using a confocal scanning laser microscope. Detail of lesion Q, subject 96-121. Scale bars:B, C, D, 10 μm.

Fig. 2.

Fig. 2.

Antigenic and morphological characteristics of oligodendrocyte precursor cells in chronic MS lesions. A, B, An O4-positive, GalC-negative oligodendrocyte precursor cell and two GalC-positive, weakly O4-positive, rounded oligodendrocytes (arrowheads) that were present in the center of lesion H (subject 96-040). C, D, Although the O4-positive (GalC-negative) cells were surrounded by large numbers of GFAP-positive filaments, confocal laser-scanning microscopic analysis suggested that they themselves lacked GFAP and thus were oligodendrocyte precursor cells. Detail of lesion Q, subject 96-121. E, F, The O4-positive (GalC-negative) oligodendrocyte precursor cells also lacked the intermediate filament vimentin (Vim).G, Low-power view of an area of lesion F (subject 96-039) that contained large numbers of O4-positive (GalC-negative) oligodendrocyte precursor cells (Table 2). This lesion also contained numerous debris-laden macrophages (Table 2), and because the debris within these cells was slightly autofluorescent, they are vaguely visible in the background. Scale bars: B, D, F, 10 μm;G, 50 μm.

Fig. 3.

Fig. 3.

O4-positive oligodendrocyte precursor cells in the chronic MS lesions failed to bind the Ki-67 antibody. Some lesions did contain some Ki-67-immunoreactive nuclei, such as the one shown here, which was present in lesion N from subject 96-074. Scale bar, 25 μm.

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