Mesenchymal stem cell therapy for the treatment of myocardial infarction

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dc.contributor.advisor Caplice, Noel M. en Gleeson, Birgitta 2015-10-20T11:21:07Z 2015-10-20T11:21:07Z 2014 2014
dc.identifier.citation Gleeson, B. 2014. Mesenchymal stem cell therapy for the treatment of myocardial infarction. PhD Thesis, University College Cork. en
dc.identifier.endpage 199
dc.description.abstract Mesenchymal stem cells (MSCs) are currently under investigation as repair agents in the preservation of cardiac function following myocardial infarction (MI). However concerns have emerged regarding the safety of acute intracoronary (IC) MSC delivery specifically related to mortality, micro-infarction and microvascular flow restriction post cell therapy in animal models. This thesis aimed to firstly identify an optimal dose of MSC that could be tolerated when delivered via the coronary artery in a porcine model of acute MI (AMI). Initial dosing studies identified 25x106 MSC to be a safe MSC cell dose, however, angiographic observations from these studies recognised that on delivery of MSC there was a significant adverse decrease in distal blood flow within the artery. This observation along with additional supportive data in the literature (published during the course of this thesis) suggested MSC may be contributing to such adverse events through the propagation of thrombosis. Therefore further studies aimed to investigate the innate prothrombotic activity of MSC. Expression of the initiator of the coagulation cascade initiator tissue factor (TF) on MSC was detected in high levels on the surface of these cells. MSC-derived TF antigen was catalytically active, capable of supporting thrombin generation in vitro and enhancing platelet-driven thrombus deposition on collagen under flow. Infusion of MSC via IC route was associated with a decreased coronary flow reserve when delivered but not when coadministered with an antithrombin agent heparin. Heparin also reduced MSC-associated in situ thrombosis incorporating platelets and VWF in the microvasculature. Heparin-assisted MSC delivery reduced acute apoptosis and significantly improved infarct size, left ventricular ejection fraction, LV volumes, wall motion and scar formation at 6 weeks post AMI. In addition, this thesis investigated the paracrine factors secreted by MSC, in particular focusing on the effect on cardiac repair of a novel MSC-paracrine factor SPARCL1. In summary this work provides new insight into the mechanism by which MSC may be deleterious when delivered by an IC route and a means of abrogating this effect. Moreover we present new data on the MSC secretome with elucidation of the challenges encountered using a single paracrine factor cardiac repair strategy. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2014, Birgitta Gleeson. en
dc.rights.uri en
dc.subject Mesenchymal stem cells en
dc.subject Myocardial infarction en
dc.subject Tissue factor en
dc.subject Heparin en
dc.subject Coronary flow reserve en
dc.subject Sparcl1 en
dc.title Mesenchymal stem cell therapy for the treatment of myocardial infarction en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder Regenerative Medicine Institute, National Centre for Biomedical Engineering Science, National University of Ireland, Galway en
dc.description.status Not peer reviewed en Biosciences Institute en Medicine en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
dc.internal.conferring Autumn Conferring 2014

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© 2014, Birgitta Gleeson. Except where otherwise noted, this item's license is described as © 2014, Birgitta Gleeson.
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