Ischaemic stroke occurs as a result of a blockage in one of the brain’s arteries, leading to neuronal injury and death. Although stroke is a major cause of death and disability, there is no widely available treatment. Inflammation occurs in the brain and in the periphery following stroke, and both contribute to the ischaemic damage. Leukocytes such as neutrophils are key mediators of brain damage and inflammation, particularly in the presence of systemic inflammatory challenges such as interleukin-1 (IL-1). Tumor necrosis factor-stimulated gene 6 (TSG-6) is a potent inhibitor of neutrophil migration, and also modulates the immune response by dampening expression of cytokines and stabilising the extra-cellular matrix (ECM). Mesenchymal stem cells (MSCs) have shown immunomodulatory actions in many inflammatory conditions, and their benefit has often been attributed to the production of TSG-6. This work aimed to evaluate the potential of TSG-6 and TSG-6-expressing MSCs as therapies in cerebral ischaemia, and to investigate the expression profile of endogenous TSG-6 in response to stroke. Mice were subjected to middle cerebral artery occlusion (MCAo) followed by reperfusion. We investigated whether IL-1-induced acute brain injury after stroke is reversed by TSG-6, and long-term recovery was evaluated in mice treated with TSG-6 or MSCs. Functional outcomes were assessed, and brains were sectioned and stained for analysis of lesion volume, haemorrhagic transformation, blood-brain barrier (BBB) disruption and neutrophil infiltration. The expression profile of TSG-6 was evaluated in mice allowed to recover for 4h, 24h, 3, 5 or 7 days. TSG-6 expression was determined by quantitative PCR and immunohistochemistry. Treatment with TSG-6 reduced IL-1-induced neutrophil infiltration into the striatum, and led to decreased BBB disruption and haemorrhagic transformation at 24h. Treatment with TSG-6 in the absence of a systemic inflammatory challenge had no significant effect on lesion volume, BBB disruption or haemorrhagic transformation after 7 days reperfusion, however thalamic neutrophil infiltration was significantly reduced. Treatment with human MSCs had no significant effect on behavioural or histological outcomes, however a heightened inflammatory response in MSC-treated mice suggested rejection of the cells by the murine immune system. TSG-6 expression peaked in the ischaemic hemisphere at 5 days post-reperfusion, and was associated with astrocytes in the glial scar surrounding the infarcted tissue. TSG-6 might be a promising therapy for the treatment of stroke in the presence of systemic inflammation. TSG-6-expressing MSCs might provide a broader therapeutic potential, and further work should optimise experimental conditions to prevent rejection of the cells. Expression of TSG-6 within the glial scar suggests a potential role in repair and recovery following ischaemic stroke. Modulating the peripheral immune response remains an attractive and accessible therapeutic target for the treatment of cerebral ischaemia.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607045 |
| Date | January 2013 |
| Creators | Buggey, Hannah |
| Contributors | Allan, Stuart; Denes, Adam |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/exploring-the-role-of-tumor-necrosis-factorstimulated-gene-6-in-experimental-ischaemic-stroke(383d1e5a-f0ee-49ef-8935-76d1ad83629e).html |
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