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Investigating the role of the mesenchymal stem cell secretome in promoting recovery after ischaemic stroke
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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Abstract
Stroke is a major global health problem with limited treatment options. Mesenchymal stem cells (MSCs) hold great potential as a novel regenerative therapy for stroke having previously been shown to promote repair and functional recovery in rodent models of cerebral ischaemia. This is increasing evidence that much the beneficial effects observed are mediated by the MSC secretome, collective term for the vast array of chemokines, cytokines and growth factors secreted by the cells. The aim of this doctoral thesis therefore was to further investigate the role of the MSC secretome in promoting repair after ischaemic stroke. The potential of in vitro preconditioning strategies to increase the efficacy of an MSC therapy was explored. It was found that priming human bone marrow-derived MSCs with interleukin-1 alpha (IL-1alpha), a pro-inflammatory cytokine, increased secretion of granulocyte-colony stimulating factor (G-CSF). Conditioned medium derived from IL-1alpha primed cells led to decreased secretion of tumour necrosis factor-alpha (TNF-alpha and IL-6 from lipopolysaccharide (LPS)-stimulated microglia. Building upon this work, the efficacy of conditioned medium was assessed in ischaemic stroke using the intraluminal filament model of middle cerebral artery occlusion (MCAO). In the initial study, conditioned medium was administered to mice at the time of stroke. This had a neuroprotective effect leading to reduction (30%) in lesion volume and modest improvements in 28-point neurological score and nest building performance at days 2 and 4 respectively compared with the vehicle treated group. Delaying administration to 24 h post-stroke led to increased nest building scores at day 9 and significantly improved neurological scores from day 7 onwards independently of neuroprotection. In conclusion while future work is required to determine the mechanisms of action and define which mediators are responsible for promoting repair, the MSC secretome has great potential as therapy for ischaemic stroke.