Abstract
Vimentin is an intermediate filament (also known as nanofilament) protein expressed in several cell types of the central nervous system, including astrocytes and neural stem/progenitor cells. Mutation of the vimentin serine sites that are phosphorylated during mitosis (VIMSA/SA) leads to cytokinetic failures in fibroblasts and lens epithelial cells, resulting in chromosomal instability and increased expression of cell senescence markers. In this study, we investigated morphology, proliferative capacity, and motility of VIMSA/SA astrocytes, and their effect on the differentiation of neural stem/progenitor cells. VIMSA/SA astrocytes expressed less vimentin and more GFAP but showed a well-developed intermediate filament network, exhibited normal cell morphology, proliferation, and motility in an in vitro wound closing assay. Interestingly, we found a two- to fourfold increased neuronal differentiation of VIMSA/SA neurosphere cells, both in a standard 2D and in Bioactive3D cell culture systems, and determined that this effect was neurosphere cell autonomous and not dependent on cocultured astrocytes. Using BrdU in vivo labeling to assess neural stem/progenitor cell proliferation and differentiation in the hippocampus of adult mice, one of the two major adult neurogenic regions, we found a modest increase (by 8%) in the fraction of newly born and surviving neurons. Thus, mutation of the serine sites phosphorylated in vimentin during mitosis alters intermediate filament protein expression but has no effect on astrocyte morphology or proliferation, and leads to increased neuronal differentiation of neural progenitor cells.
Highlights
The intermediate filament system of astrocytes is a dynamic integrator of cellular functions under physiological conditions and plays an important role in times of cellular stress as well as in the subsequent regenerative processes [1,2,3,4,5,6]
Immunolabeling of glial fibrillary acidic protein (GFAP), nestin, and vimentin showed bundles of intermediate filaments that did not differ between VIMWT/WT and VIMSA/SA astrocytes (Fig. 1a)
Combined immunolabeling of VIMWT/WT and VIMSA/SA astrocytes with antibodies against GFAP and vimentin, or nestin and vimentin, visualized comparable networks of intermediate filament bundles with a comparable contribution of the respective intermediate filament proteins (Fig. 1a)
Summary
The intermediate filament system (known as nanofilament system) of astrocytes is a dynamic integrator of cellular functions under physiological conditions and plays an important role in times of cellular stress as well as in the subsequent regenerative processes [1,2,3,4,5,6]. Whereas the upregulation of intermediate filament proteins in astrocytes is important for the confinement of the lesion area in brain injury, ischemic stroke, retinal ischemia, or spinal cord injury, it inhibits some of the regenerative processes later on [4, 5]. We demonstrated that in GFAP−/−Vim−/− mice, retinal grafts can better integrate [14], Mol Neurobiol (2018) 55:5478–5489 differentiation of transplanted neural stem cells into neurons and astrocytes is enhanced [15], and hippocampal neurogenesis is increased in naïve mice [16], after neonatal hypoxic-ischemic injury [17], or after neurotrauma [16]. We investigated whether the vimentin phosphorylation deficit in VIMSA/SA mice alters astrocyte morphology, proliferative capacity, and motility, and whether the phosphovimentin-deficient astrocyte niche affects neuronal differentiation of neural progenitor cells in vitro and neurogenesis in vivo
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