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Title: Elucidating the role of Quaking (QKI) during vascular cell differentiation from pluripotent stem cells
Author: Cochrane, Amy
ISNI:       0000 0004 6425 0543
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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The ability to derive endothelial cells (ECs) and smooth muscle cells (SMCs) from induced pluripotent stem cells (IPSCs) holds hugh therapeutic potential for cardiovascular disease. This study elucidates the precise role of the RNA-binding protein Quaking (QKI) and its alternative splicing isoforms during this vascular cell differentiation. iPSCs represent an attractive cellular approach for regenerative medicine today since they can be used to generate patient-specific therapeautic cells towards autologous cell therapy. Understanding how RNA-binding proteins can improve differentiation efficiency is vital for developing cell therapy for the treatment or prevention of vascular diseases. This study uses iPSCs differentiate towards ECs and demonstrates that QKI alternative splicing isoform, QKI-5 is essential for EC differentiation. QKI-5 regulates CD144 stabilisation, vascular endothelial growth factor (VEGF) receptor transcriptional activation and VEGF secretion through signal transducer and activator of transcription 3 (STAT3) activation and phosphorylation. Importantly, QKI-5 overexpression in ECs derived from iPSCs improved vascularization in angiogenesis assays and experimental models of hind limb ischemia. In parallel, the alternative splicing isoform, QKI-6, has been shown to be implicated in the differentiation of SMCs from iPSCs. Notably, QKI-6 is shown to be involved in the splicing of histone deacetylase 7 (HDAC7) resulting in the downstream events known to indice SMC differentiation. These results highlight a dear functional benefit of QKI during vascular development. This supports the idea that understanding the underlying mechanisms of EC and SMC differentiation will advance stem cell regenerative therapy towards a reality in the treatment of cardiovascular diseases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available