Human pluripotent stem cell models of heart development and disease

Elliott DA

Murdoch Childrens Research Institute.

Congenital heart disease is the most common form of birth defect, with a prevalence approaching 1 in 100 children. Although the etiologies underlying congenital heart disease and cardiovascular disease differ, the development of new treatments for either condition will be critically dependent on a detailed understanding of how the human heart is formed and how it functions at the cellular and molecular level. Human pluripotent stem cell (hPSC) derived cardiomyocytes are the only tractable platform for illuminating the fine detail of the genetic networks that control human cardiomyocyte cell biology. We have developed a cellular framework to investigate the genetic regulation of human cardiac cell lineage specification. We are now utilizing these reagents and technologies to study congenital heart disease using differentiating hPSCs. In particular, we are examining the role of the important cardiac transcription factor NKX2-5 to determine the molecular mechanisms underlying congenital heart disease in individuals with NKX2-5 mutations. We have shown that NKX2-5 is essential for the activation of the ventricular cardiomyocyte commitment marker VCAM1 and for the coordinated contraction of hPSC derived cardiac monolayers. Through RNA-seq and ChIP-seq HEY2 was identified as a downstream mediator of NKX2-5. HEY2 was able to restore both VCAM1 expression and contractile synchronicity to NKX2-5 deficient cardiomyocytes. Thus, NKX2-5 and HEY2 are components of the genetic network controlling human ventricular cardiomyocyte differentiation.