PhD Programme for Clinicians at the University of Cambridge: "Generation of 'translation ready' ground state human induced pluripotent stem cells and cardiomyocytes as a prelude to disease modelling in cardiovascular medicine". (360G-Wellcome-087009_Z_08_A)

The generation of induced pluripotent stem cells from somatic cells brings the possibility of translational applications in regenerative medicine, disease modelling and drug screening a step closer. However current derivation methods remain inefficient, unpredictable and clinically unsafe. In order to maximise the translational potential of iPS cells in clinical medicine, these methods must be optimised. I will establish a 'translation ready' iPS cell by identifying the most efficiently reprogrammable of a number of human somatic cells including dermal fibroblasts, keratinocytes and adipose tissue. Clinically safer non-viral gene delivery methods will also be developed. Attempts will then be made to capture and maintain ground state pluripotency by deriving iPS cells in variations of the recently described 2i/LIF conditions shown to suppress early differentiation signals, reduce epigenetic restriction and improve iPS derivation efficiency in mouse and rat iPS cells. The resulting iPS cells will be characterised in terms of gene expression, epigenetic profiles and differentiation potential. Ultimately, iPS cells derived from a patient with a known monogenetic cardiac channelopathy such as long QT syndrome will be differentiated into cardiomyocytes and functionally examined by patch clamp in collaboration with electrophysiology colleagues to prove their suitability for the modelling of monogenetic cardiac channelopathies.