Activation of the subventricular zone in multiple sclerosis: Evidence for early glial progenitors

Abstract

In multiple sclerosis (MS), oligodendrocyte and myelin destruction lead to demyelination with subsequent axonal loss. Experimental demyelination in rodents has highlighted the activation of the subventricular zone (SVZ) and the involvement of progenitor cells expressing the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the repair process. In this article, we studied the distribution of early PSA-NCAM(+) progenitors in the SVZ and MS lesions in human postmortem brains. Compared with controls, MS SVZ showed a 2- to 3-fold increase in cell density and proliferation, which correlated with enhanced numbers of PSA-NCAM(+) and glial fibrillary acidic protein-positive (GFAP(+)) cells. PSA-NCAM(+) progenitors mainly were Sox9(+), and a few expressed Sox10 and Olig2, markers of oligodendroglial specification. PSA-NCAM(+) progenitors expressing Sox10 and Olig2 also were detected in demyelinated MS lesions. In active and chronic active lesions, the number of PSA-NCAM(+) progenitors was 8-fold higher compared with chronic silent lesions, shadow plaques, and normal-appearing white matter. In active and chronic active lesions, PSA-NCAM(+) progenitors were more frequent in periventricular lesions (30-50%) than in lesions remote from the ventricular wall. These data indicate that, as in rodents, activation of gliogenesis in the SVZ occurs in MS and suggest the mobilization of SVZ-derived early glial progenitors to periventricular lesions, where they could give rise to oligodendrocyte precursors. These early glial progenitors could be a potential target for therapeutic strategies designed to promote myelin repair in MS.