Supervisory team members: Dr David Monk, Dr Iain Macaulay
As we age our ability to regenerate tissue reduces significantly. This is particularly true for the human heart, which has virtually no ability to regenerate postnatally or after disease processes such as myocardial infarction (MI), predominately due to poor revasculariation, which prevents repair of damaged myocardium. The endocardium is the layer of endothelial cells (ECs) lining the inner surfaces of the heart chambers. It has key roles in chamber and heart valve development, cardiomyocyte maturation and coronary vessel regeneration post-myocardial infartion (MI). However, our understanding of the endocardium's capacity to contribute to these processes and our ability to harness its potential in regenerative medicine has been hampered by our inability to culture human endocardium long-term in vitro and the lack of any endocardial cell lines.
We have developed such a model using pluripotent stem cells (PSC). Our PSC-derived endocardial cells (PSC-endocs) express markers consistent with a mature endocardial-like identity, can transdifferentiate into coronary EC-like cells (PSC-cECs), undergo an endothelial to mesenchymal transition to express genes present during valvulogeneis and enhance the force generation of cardiomyocytes in engineered heart tissue. Our initial analyses show that the PSC-endocs population is heterogenous and subpopulations are likely to have different differentiation and regenerative capacities. It is therefore important to characterise these populations, so that we might harness their potential in regenerative medicine.
The objectives of this PhD are:
- Undertanding PSC-endoc population heterogeneity and generating a reporter line in human pluripotent stem cells that allow us to distinguish and sort subpopulations of these cells for further characterisation.
- Performing transcriptomic analyses of GATA4+ and GATA4- PSC-endocs to obtain a deeper characterisation of each population and test their differentiation and regenerative capacity.
- Identification of pathways that regulate the transdifferentiation of endocardial cells to cECs, and may therefore enhance cariovascular regeneration