In vitro modeling of cell types in cardiogenesis and congenital heart disease

Congenital heart defects (CHD) are present in nearly 1 % of live births and are a leading cause of infant mortality. Despite advances in genome sequencing technologies and an increased understanding of the genes necessary for heart development, the etiology of a majority of CHD cases remains undefined. Recent breakthroughs in single-cell genomics, lineage tracing, and live imaging in animal models of cardiogenesis have revealed the precise spatiotemporal dynamics of discrete cell types in heart development. Here, I review how these findings have informed the development of new human pluripotent stem cell methods to generate a diverse range of cells in cardiogenesis. A key unifying theme is that multipotent cardiac progenitor cells are extraordinarily responsive to slight changes to signaling factors administered at various stages of cardiac differentiation. I highlight how the ability to make a range of cardiac cell types can be used to define context specific mechanisms of CHD. I then describe how in vitro human models of cardiogenesis are especially important in cases of severe forms of CHD, such as single ventricle disorders, for which the complex genetic underlying mechanisms are poorly defined and animal models are lacking.