| 1. |
- Widestrand, Åsa, 1978, et al.
(författare)
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Increased neurogenesis and astrogenesis from neural progenitor cells grafted in the hippocampus of GFAP-/- Vim-/- mice.
- 2007
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 25:10, s. 2619-27
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Tidskriftsartikel (refereegranskat)abstract
- After neurotrauma, ischemia, or neurodegenerative disease, astrocytes upregulate their expression of the intermediate filament proteins glial fibrillary acidic protein (GFAP), vimentin (Vim), and nestin. This response, reactive gliosis, is attenuated in GFAP(-/-)Vim(-/-) mice, resulting in the promotion of synaptic regeneration after neurotrauma and improved integration of retinal grafts. Here we assessed whether GFAP(-/-)Vim(-/-) astrocytes affect the differentiation of neural progenitor cells. In coculture with GFAP(-/-)Vim(-/-) astrocytes, neural progenitor cells increased neurogenesis by 65% and astrogenesis by 124%. At 35 days after transplantation of neural progenitor cells into the hippocampus, adult GFAP(-/-)Vim(-/-) mice had more transplant-derived neurons and astrocytes than wild-type controls, as well as increased branching of neurite-like processes on transplanted cells. Wnt3 immunoreactivity was readily detected in hippocampal astrocytes in wild-type but not in GFAP(-/-)Vim(-/-) mice. These findings suggest that GFAP(-/-)Vim(-/-) astrocytes allow more neural progenitor cell-derived neurons and astrocytes to survive weeks after transplantation. Thus, reactive gliosis may adversely affect the integration of transplanted neural progenitor cells in the brain. Disclosure of potential conflicts of interest is found at the end of this article.
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| 2. |
- Widestrand, Åsa, 1978
(författare)
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The effect of astrocytes and reactive gliosis on neurogenesis and astrogenesis in mice
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Wilhelmsson, Ulrika, 1970, et al.
(författare)
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Astrocytes negatively regulate neurogenesis through the Jagged1-mediated notch pathway.
- 2012
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 30:10, s. 2320-9
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Tidskriftsartikel (refereegranskat)abstract
- Adult neurogenesis is regulated by a number of cellular players within the neurogenic niche. Astrocytes participate actively in brain development, regulation of the mature central nervous system (CNS), and brain plasticity. They are important regulators of the local environment in adult neurogenic niches through the secretion of diffusible morphogenic factors, such as Wnts. Astrocytes control the neurogenic niche also through membrane-associated factors, however, the identity of these factors and the mechanisms involved are largely unknown. In this study, we sought to determine the mechanisms underlying our earlier finding of increased neuronal differentiation of neural progenitor cells when cocultured with astrocytes lacking glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-) Vim(-/-) ). We used primary astrocyte and neurosphere cocultures to demonstrate that astrocytes inhibit neuronal differentiation through a cell-cell contact. GFAP(-/-) Vim(-/-) astrocytes showed reduced endocytosis of Notch ligand Jagged1, reduced Notch signaling, and increased neuronal differentiation of neurosphere cultures. This effect of GFAP(-/-) Vim(-/-) astrocytes was abrogated in the presence of immobilized Jagged1 in a manner dependent on the activity of γ-secretase. Finally, we used GFAP(-/-) Vim(-/-) mice to show that in the absence of GFAP and vimentin, hippocampal neurogenesis under basal conditions as well as after injury is increased. We conclude that astrocytes negatively regulate neurogenesis through the Notch pathway, and endocytosis of Notch ligand Jagged1 in astrocytes and Notch signaling from astrocytes to neural stem/progenitor cells depends on the intermediate filament proteins GFAP and vimentin.
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| 4. |
- Wilhelmsson, Ulrika, 1970, et al.
(författare)
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The role of GFAP and vimentin in learning and memory
- 2019
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Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 400:9, s. 1147-1156
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Tidskriftsartikel (refereegranskat)abstract
- Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke. However, GFAP and Vim were also linked to neural plasticity and regenerative responses in healthy and injured brain. Mice deficient for GFAP and vimentin (GFAP(-/-)Vim(-/-)) exhibit increased post-traumatic synaptic plasticity and increased basal and post-traumatic hippocampal neurogenesis. Here we assessed the locomotor and exploratory behavior of GFAP(-/-)Vim(-/-) mice, their learning, memory and memory extinction, by using the open field, object recognition and Morris water maze tests, trace fear conditioning, and by recording reversal learning in IntelliCages. While the locomotion, exploratory behavior and learning of GFAP(-/-)Vim(-/-) mice, as assessed by object recognition, the Morris water maze, and trace fear conditioning tests, were comparable to wildtype mice, GFAP(-/-)Vim(-/-) mice showed more pronounced memory extinction when tested in IntelliCages, a finding compatible with the scenario of an increased rate of reorganization of the hippocampal circuitry.
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