Mesenchymal stem cell therapy for the treatment of myocardial infarction

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dc.check.embargoformatNot applicableen
dc.check.infoNo embargo requireden
dc.check.opt-outNot applicableen
dc.check.reasonNo embargo requireden
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dc.contributor.advisorCaplice, Noel M.en
dc.contributor.authorGleeson, Birgitta
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderRegenerative Medicine Institute, National Centre for Biomedical Engineering Science, National University of Ireland, Galwayen
dc.date.accessioned2015-10-20T11:21:07Z
dc.date.available2015-10-20T11:21:07Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractMesenchymal 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.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGleeson, B. 2014. Mesenchymal stem cell therapy for the treatment of myocardial infarction. PhD Thesis, University College Cork.en
dc.identifier.endpage199
dc.identifier.urihttps://hdl.handle.net/10468/2003
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Birgitta Gleeson.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectMesenchymal stem cellsen
dc.subjectMyocardial infarctionen
dc.subjectTissue factoren
dc.subjectHeparinen
dc.subjectCoronary flow reserveen
dc.subjectSparcl1en
dc.thesis.opt-outfalse
dc.titleMesenchymal stem cell therapy for the treatment of myocardial infarctionen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorn.caplice@ucc.ie
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