Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/1547
Title: The role of endoglin in cell-mediated heart repair
Authors: Redgrave, Rachael Elizabeth
Issue Date: 2012
Publisher: Newcastle University
Abstract: Despite substantial advances in pharmacological and interventional strategies for the treatment of ischaemic heart disease and acute myocardial infarction (MI) many patients go on to develop dilated heart failure with high morbidity and mortality rates. Increasing evidence suggests that stem cells can augment re-vascularisation of the infarcted myocardium leading to improved cardiac function. However, the precise mechanisms involved are not completely understood and further work is required to realise optimised cell based therapy. The aim of this project was to investigate the role of endoglin, a pro-angiogenic TGF co-receptor, in bone marrow (BM)-derived endothelial progenitor cells (EPCs) and in cardiac-resident cardiosphere-derived cells (CDCs) using mouse models. I hypothesised that endoglin acts as a key marker and functional regulator of the pro-angiogenic repair properties of these stem cells and that manipulating TGF signalling by controlling endoglin levels could provide a better understanding of the properties of these cells, with the longer term goal of developing more effective revascularisation therapies. My data show that inhibiting TGF /Alk5 signalling in vitro increases EPC yield from both endoglin heterozygous and wild-type BM cells. In addition, although endothelial specific knock-down of endoglin in vivo led to increased endoglin expression in cells from the BM, these cells did not incorporate into endoglin depleted heart or lung vasculature. I also showed that endoglin deficiency results in a significant reduction in EPC yield from BM cells and inducible endoglin depletion in CDCs (using a conditional endoglin knock-out mouse model) impairs cellular proliferation and migration in vitro alongside up-regulated TGF /Alk5 signalling. Furthermore, injection of wild-type CDCs into the ischaemic border zone of the heart, following coronary artery occlusion in a mouse MI model, led to an increased angiogenic response at 4 weeks. This response was significantly reduced when endoglin depleted cells were transplanted. However both wild-type and endoglin depleted CDCs were able to rescue heart function, as measured using cardiac MRI. In conclusion, the results of this thesis provide evidence of the important roles that endoglin and TGF signalling play in promoting angiogenesis in tissue repair. Further advances in this field could aid in the development of more effective cell therapies for MI patients.
Description: PhD Thesis
URI: http://hdl.handle.net/10443/1547
Appears in Collections:Institute of Human Genetics

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