The effect of astrocytes and reactive gliosis on neurogenesis and astrogenesis in mice

Sammanfattning: Astrocytes are the most common cell type in mammalian central nervous system (CNS). Glial fibrillary acidic protein (GFAP) and vimentin constitute intermediate filaments (known also as nanofilaments), a part of the cytoskeleton, in astrocytes. In damaged CNS, astrocytes become reactive and increase the expression of GFAP and vimentin and alter the expression of the host of other genes, a process referred to as reactive gliosis. Reactive astrocytes have a neuroprotective effect in neurotrauma or brain ischemia, but they have also been shown to inhibit CNS regeneration. GFAP-/-Vim-/- mice are deficient in astrocyte intermediate filaments and after neurotrauma or in brain ischemia show less prominent reactive gliosis than wildtype mice. Mild reactive gliosis occurs in the hippocampus of healthy aging individuals, both in rodents and humans. Neurogenesis in the dentate gyrus of the hippocampus is known to decline during life. We assessed the effect of age-related reactive gliosis on hippocampal neurogenesis in GFAP-/-Vim-/- and wildtype mice (Paper I). We found that attenuated reactive gliosis in aged GFAP-/-Vim-/- mice was linked to higher hippocampal cell proliferation and neurogenesis. Our data suggest that age-related reactive gliosis may be a cause for declining neurogenesis in aging brain. Our research group previously showed that the attenuation of reactive gliosis in GFAP-/-Vim-/- mice improved integration of neural grafts. Here, we addressed whether GFAP-/-Vim-/- astrocytes affect neural progenitor cell differentiation in vitro and survival and differentiation of grafted neural progenitor cells in a neurogenic niche in the brain (Paper II). Using cocultures of neural progenitor cells and astrocytes, we found that GFAP-/-Vim-/- astrocytes increased the number of neural progenitor-derived neurons and astrocytes. When adult hippocampal progenitor cells were grafted in the hippocampal region, GFAP-/-Vim-/- recipients showed more graft-derived astrogenesis and neurogenesis. These findings suggest that attenuation of reactive gliosis may be a suitable strategy for enhancing adult neurogenesis and for increasing the efficiency of neural progenitor cell transplantation. In the next study (Paper III), we found that the baseline and posttraumatic hippocampal neurogenesis and some aspects of learning and memory were improved in GFAP-/-Vim-/- mice compared to wildtype controls. Moreover, we provide evidence that astrocytes constitute an important niche for production of new neural cells in the adult hippocampus.