Investigating the mechanisms of epigenetic remodelling and RNA binding protein mediated splicing in vascular cell programming for cardiovascular therapy

  • Rachel Caines

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

The ability to create rejuvenated, functional and safe vascular cells could have great therapeutic implications in diseases such as peripheral arterial disease, ischaemia and myocardial infarction, but key underlying mechanisms of vascular cell production from induced pluripotent stem cells (iPSCs) must be understood to maximise the success of these novel therapies.

This thesis uncovers novel transcriptional and epigenetic mechanisms of endothelial cell (EC) and vascular smooth muscle cell (VSMC) differentiation from iPSCs through the regulation of SET Similar Protein (SETSIP) and the RNA Binding Protein Quaking (QKI), respectively.

SETSIP was found to increase EC differentiation from iPSCs while impacting on histone acetylation. The SIRT1 inhibitor, Ex-527, was found to regulate SETSIP, providing a small molecule approach by which to manipulate EC differentiation without the need for exogenous gene overexpression. A novel 10 amino acid peptide derived from SETSIP was also shown to have remarkable effects on in vitro and in vivo angiogenesis.

Quaking alternative splicing isoform 6 (QKI-6) was found to be a critical regulator of iPS-VSMC differentiation through the regulation of Histone Deacetylase 7 alternative splicing. We produced a robust and effective combination cell therapy through the administration of QKI-5 derived ECs with QKI-6 VSMCs.
The discovery of three novel regulators for the differentiation of iPSCs to vascular cells is a significant step forward for regenerative medicine. The ability to generate defined protocols through the use of small molecules and growth factors will lead to more successful and efficient therapies for translation to the clinic.
Date of AwardDec 2019
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsBritish Heart Foundation
SupervisorAndriana Margariti (Supervisor) & David Grieve (Supervisor)

Cite this

'