Abstract

Cardiovascular disease (CVD) is the leading cause of death globally, in 2013 it was responsible for 30% of all deaths worldwide. It has been shown that endothelial dysfunction is a major pathological mechanism that precedes CVD, yet these damaged endothelial cells (ECs) display poor regenerative capabilities. Current therapy is inadequate or unsuitable for a significant number of patients, however it is thought that the ability to replace damaged ECs could serve as a valuable therapeutic option for the future. Recent capability to generate induced pluripotent stem cells (iPSCs) from adult cells and differentiate these towards ECs holds great promise in the area of regenerative medicine. Nevertheless, the differentiation process involved is complex and not fully understood. An appreciation of a variety of molecular mechanisms is required in order to enhance protocols that could be replicated for novel therapies. This project has derived ECs from iPSCs using a reliable protocol. Results here confirmed successful differentiation with an up-regulation in important endothelial markers at the mRNA level alongside positive immunofluorescent staining. These differentiated cells were characteristically similar to mature ECs. In order to expose underlying mechanisms of EC differentiation, the novel gene SETSIP was shown to be upregulated during this process. Further investigation to stimulate differentiating cells with a SETSIP peptide noted an induction in endothelial markers. Finally, experiments involving epigenetic drugs induced changes in both endothelial marker and SETSIP expression. This project has elucidated the role of SETSIP and data shown here may be important in advancing therapeutic potential through the development of more robust protocols concerning EC differentiation.