GFAP delta-positive cells in the subventricular zone in MS: activation and migration of multipotent progenitors?
01 / 2008 - 01 / 2009
Stichting MS Research
Recently we described an alternative splice variant of glial fibrillary acid protein (GFAP), GFAP-delta, in a characteristic subpopulation of astrocytes in the subpial and subependymal layers of the human brain. GFAP-delta expression was especially pronounced in the subventricular zone (SVZ) of the lateral ventricles, a region known to contain GFAP+ multipotent progenitors giving rise to new neurons, astrocytes and oligodendrocytes. This location, together with the fact that GFAP-delta+ cells also express GFAP-alpha, strongly suggests that these cells are GFAP+ multipotent progenitors. Transfection studies showed that GFAP-delta suppresses GFAP filament formation, thereby possibly influencing the astrocytic cytoskelal and the migratory properties of these cells. Interestingly, a recent pilot showed an impressive expansion of the population of GFAP-delta+ cells in the SVZ in MS. GFAP-delta+ cells were grouped together in a way highly suggestive for extensive cell proliferation. Also, within nearby situated periventricular MS lesions many GFAP-delta+ cells were seen. In experimental allergic encephalomyelitis (EAE) it has been shown that progenitors are mobilized from the SVZ to undergo oligodendrogenesis. One study in MS shows upregulation of P75NTR expressing oligodendroglial progenitors adjacent to the SVZ in one case of multiple sclerosis (MS), but about the possible proliferation of progenitors in the SVZ in MS and their relation to nearby MS lesions nothing is known. It has been suggested that these progenitors may act as a source of new oligodendrocytes and astrocytes for remyelination and scar formation. In the current project we propose to further investigate GFAP-delta+ cells in the SVZ in relation to MS lesions and we aim to address the following questions: (i) is the SVZ enlarged in MS and is this enlargement dependent on nearby situated MS lesions (ii) what is the phenotype the GFAP+ cells, i.e. what other cell markers do they express iii. do GFAP-delta+ cells in the SVZ proliferate, and (iv) are there indications that GFAP+ cells migrate from the SVZ to nearby MS lesions?