The adult neural stem cell niche in ischaemic stroke
<p>Ischaemic stroke is a major cause of mortality and chronic disability for which there is no effective treatment. The subventricular zone (SVZ) is an adult neurogenic niche which mediates limited endogenous repair following stroke. To harness this phenomenon for therapy, it is important to u...
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| Format: | Thesis |
| Language: | English |
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2011
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| _version_ | 1797079909507530752 |
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| author | Young, C |
| author2 | Szele, F |
| author_facet | Szele, F Young, C |
| author_sort | Young, C |
| collection | OXFORD |
| description | <p>Ischaemic stroke is a major cause of mortality and chronic disability for which there is no effective treatment. The subventricular zone (SVZ) is an adult neurogenic niche which mediates limited endogenous repair following stroke. To harness this phenomenon for therapy, it is important to understand how the SVZ niche is altered in stroke, and the processes that recruit neural precursors to the site of injury, which becomes a <em>de facto</em> neurogenic niche. Galectin-3 (Gal-3) is a β-galactoside binding protein involved in cellular adhesion, inflammation and tumour metastasis. Gal-3 is specifically expressed in the SVZ and maintains neuroblast migration to the olfactory bulb, although its role in post-stroke neurogenesis is not well-understood. Therefore, this project aimed to (1) characterise the cytoarchitecture of the SVZ in response to stroke, and (2) examine the role of Gal-3 in stroke outcome and tissue remodelling, and test the hypothesis that Gal-3 is required for neuroblast ectopic migration into the ischaemic striatum.</p> <p>Using the intraluminal filament model of middle cerebral artery occlusion (MCAO) in mice, and whole mounts of the lateral ventricular wall, significant SVZ reactive astrocytosis and increased vascular branching were observed, thereby disrupting the neuroblast migratory scaffold. Stroke increased SVZ cell proliferation without increase in cell death. Post-stroke ependymal cells were enlarged and non-proliferative, and assumed a reactive astroglial phenotype, expressing <em>de novo</em> high levels of glial fibrillary acidic protein. This was associated with focal planar cell polarity misalignment, and turbulent and decreased rate of cerebrospinal fluid flow. These findings demonstrate significant changes in multiple SVZ cell types which are positioned to influence post-stroke neurogenesis and regulation of the neural stem cell niche</p> <p>Gal-3 was up-regulated in the ischaemic brain and ipsilateral SVZ. To elucidate the role of Gal-3 after stroke, MCAO was performed in wildtype and Gal-3 null (Gal-3<sup>-/-</sup>) mice, and parameters of stroke outcome and post-stroke neurogenesis compared. The deletion of Gal-3 did not affect infarct volumes or neurological outcomes, although neuroblast migration into the ischaemic striatum was increased in Gal-3<sup>-/-</sup> brains. Gal-3<sup>-/-</sup> mice failed to mount an angiogenic response in the ischaemic striatum, and this was associated with lower levels of vascular endothelial growth factor (VEGF) and increased anti-angiogenic protein levels. Loss of Gal-3 further disrupted the pro-proliferative neural-vascular interaction at the basement membrane. The current data indicate that Gal-3 is a pleiotropic molecule which has distinct roles in both the SVZ and the post-stroke striatum as niches of adult neurogenesis. </p> |
| first_indexed | 2024-03-07T00:52:35Z |
| format | Thesis |
| id | oxford-uuid:86e6e236-047c-46d8-96e5-449a3f0505a8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:52:35Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:86e6e236-047c-46d8-96e5-449a3f0505a82022-03-26T22:07:14ZThe adult neural stem cell niche in ischaemic strokeThesishttp://purl.org/coar/resource_type/c_db06uuid:86e6e236-047c-46d8-96e5-449a3f0505a8NeuroscienceCell BiologyStrokeStem cells (clinical sciences)EnglishOxford University Research Archive - Valet2011Young, CSzele, F<p>Ischaemic stroke is a major cause of mortality and chronic disability for which there is no effective treatment. The subventricular zone (SVZ) is an adult neurogenic niche which mediates limited endogenous repair following stroke. To harness this phenomenon for therapy, it is important to understand how the SVZ niche is altered in stroke, and the processes that recruit neural precursors to the site of injury, which becomes a <em>de facto</em> neurogenic niche. Galectin-3 (Gal-3) is a β-galactoside binding protein involved in cellular adhesion, inflammation and tumour metastasis. Gal-3 is specifically expressed in the SVZ and maintains neuroblast migration to the olfactory bulb, although its role in post-stroke neurogenesis is not well-understood. Therefore, this project aimed to (1) characterise the cytoarchitecture of the SVZ in response to stroke, and (2) examine the role of Gal-3 in stroke outcome and tissue remodelling, and test the hypothesis that Gal-3 is required for neuroblast ectopic migration into the ischaemic striatum.</p> <p>Using the intraluminal filament model of middle cerebral artery occlusion (MCAO) in mice, and whole mounts of the lateral ventricular wall, significant SVZ reactive astrocytosis and increased vascular branching were observed, thereby disrupting the neuroblast migratory scaffold. Stroke increased SVZ cell proliferation without increase in cell death. Post-stroke ependymal cells were enlarged and non-proliferative, and assumed a reactive astroglial phenotype, expressing <em>de novo</em> high levels of glial fibrillary acidic protein. This was associated with focal planar cell polarity misalignment, and turbulent and decreased rate of cerebrospinal fluid flow. These findings demonstrate significant changes in multiple SVZ cell types which are positioned to influence post-stroke neurogenesis and regulation of the neural stem cell niche</p> <p>Gal-3 was up-regulated in the ischaemic brain and ipsilateral SVZ. To elucidate the role of Gal-3 after stroke, MCAO was performed in wildtype and Gal-3 null (Gal-3<sup>-/-</sup>) mice, and parameters of stroke outcome and post-stroke neurogenesis compared. The deletion of Gal-3 did not affect infarct volumes or neurological outcomes, although neuroblast migration into the ischaemic striatum was increased in Gal-3<sup>-/-</sup> brains. Gal-3<sup>-/-</sup> mice failed to mount an angiogenic response in the ischaemic striatum, and this was associated with lower levels of vascular endothelial growth factor (VEGF) and increased anti-angiogenic protein levels. Loss of Gal-3 further disrupted the pro-proliferative neural-vascular interaction at the basement membrane. The current data indicate that Gal-3 is a pleiotropic molecule which has distinct roles in both the SVZ and the post-stroke striatum as niches of adult neurogenesis. </p> |
| spellingShingle | Neuroscience Cell Biology Stroke Stem cells (clinical sciences) Young, C The adult neural stem cell niche in ischaemic stroke |
| title | The adult neural stem cell niche in ischaemic stroke |
| title_full | The adult neural stem cell niche in ischaemic stroke |
| title_fullStr | The adult neural stem cell niche in ischaemic stroke |
| title_full_unstemmed | The adult neural stem cell niche in ischaemic stroke |
| title_short | The adult neural stem cell niche in ischaemic stroke |
| title_sort | adult neural stem cell niche in ischaemic stroke |
| topic | Neuroscience Cell Biology Stroke Stem cells (clinical sciences) |
| work_keys_str_mv | AT youngc theadultneuralstemcellnicheinischaemicstroke AT youngc adultneuralstemcellnicheinischaemicstroke |