Understanding Cardiac Progenitors to deliver Regenerative Medicine and Disease Modelling

Cardiovascular disease, including damage to heart muscle, kills more people worldwide than any other illness. The cardiovascular research community aims to solve this by tackling it from multiple angles. Human pluripotent stem cell (hPSC) technology promises to underpin many translational approaches including cardiac regenerative medicine (cell therapy), heart disease modelling including congenital heart disease (CHD), and drug and gene therapy screening platforms. However, a major roadblock holding back medical advances is the uncontrolled and heterogeneous differentiation of hPSCs, which is commonly observed in practice and is partly due to our poor understanding of the gene regulatory mechanisms coordinating development. The progenitors of the heart are known to acquire their identity and lineage assignment early in embryogenesis very soon after the mesoderm starts to form. This research will focus on accurately controlling this early step of hPSC differentiation by understanding the function of the transcription factor HAND1 and its relationship with other transcription factors expressed in mesoderm, particularly the 'cardiac master regulator' MESP1. Using CRISPR-Cas9 screening technology we will also investigate the gene regulatory elements (enhancers and silencers) of HAND1 and discover how its expression is turned on and tuned, obtaining practical knowledge for its better control, and revealing fundamental mechanisms of mesoderm fate determination.
Our increasingly detailed molecular profiling of cardiac cell development in our in vitro stem cell model presents a particular opportunity to gain insight on the genetic causes of CHD. With a growing number of DNA variants clinically associated with CHD, the genotype-phenotype relationship is currently beyond our understanding in most cases. Again, drawing on CRISPR-Cas9 screening technology, the final objective of this research is to test how genes implicated in CHD may affect the specification, self-renewal, or differentiation of cardiac progenitors. This information will add additional layers of knowledge to our understanding of the mechanisms behind the cardiac lineage fate map. The testing platform will also be of clinical importance for supporting the genetic diagnosis of CHD and delivering personalised medicine.
Combining its overlapping components, in sum this work will deliver a step change in stem cell research for applications in cardiology. It will uncover how the different lineages of cardiac progenitors are programmed and how seemingly linear gradients in transcription factor expression can be transformed into discrete and robust fate choices. It will uncover en masse how mutations associated with CHD impact the cardiac cell development process. These advances will catalyse a range of translational applications in cardiac regenerative medicine and the modelling of CHD to help tackle the global burden of heart disease.