Arsenio Dos Santos Ruivo, Jorge Manuel; (2018) The use of miR-92a inhibitor to enhance endothelial progenitor cell-mediated regeneration of injured arteries. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Restenosis, a pathological condition characterised by neointima formation and lumen narrowing, can occur in some patients submitted to percutaneous coronary intervention. Reducing its incidence remains an important medical issue. Circulating endothelial precursor cells (EPCs) home to the vascular injury site and contribute to re-endothelialisation and neointima attenuation. However, the engraftment and repair capacity of EPCs from patients with cardiovascular disease are typically impaired. Priming strategies to increase EPCs’ engraftment may improve post-injury outcomes. Antiangiogenic miR-92a is upregulated in EPCs of cardiovascular patients, contributing to their reduced regenerative capacity. It was hypothesized that miR-92a antagonism in EPCs could result in a more favourable angiogenesis profile, with the rationale of developing a future functional priming strategy before cell transplantation which could lead to increased engrafting/thriving and accelerated re-endothelialisation on injured segments, hence, contributing towards post-PCI restenosis prevention. The aims of the work were: 1) to differentiate and characterise CD34+ -derived late-outgrowth EPCs from an enriched progenitor human source; 2) to characterise target gene expression and demonstrate in vitro the functional priming following the treatment of EPCs with miR-92a inhibitor and relate it to the ensueing integrin α5 subunit (ITGA5) derepression. A human EPC culture was obtained following differentiation of cord blood CD34+ cells. miR-92a inhibitor treatment using oligofectamine in CD34+ -derived late-outgrowth EPCs revealed proangiogenic,-migratory,-proliferative, and -adhesive effects in vitro, which was accompanied by the derepression of integrin α5 (ITGA5). Remarkably, siRNA ITGA5 abrogated the enhanced matrix adhesion in primed EPCs, highlighting the role of the miR-92a downstream target in EPC engraftment. Preliminary intraluminal transplantation results suggested enhanced engraftment capacity of primed EPCs in the rat carotid balloon angioplasty model.

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