Multi-lineage cardiac model recapitulates human cardiogenesis and heart defects

Congenital heart defects constitute the leading cause of human fetal death, however the underlying mechanisms of most cardiac defects remain unknown. The ability to generate in vitro cardiac models mimicking significant aspects of native heart development is a prerequisite for disease modeling. Here, we established a 2D cardiac platform that equivalent of human fetal heart with pluripotent stem cells (hPSCs). Through the precise manipulation of retinoic acid (RA) signaling, we recapitulated the anterior-posterior patterning found in embryogenesis. By lineage tracing analyses and single-cell transcriptomic profiling, we described the lineage relationships between distinct populations and the developmental potentials of heart-field-specific progenitors. Comparisons of hPSC-derived and gastrulating human hearts enabled the identification of in vivo-like cardiac molecular characteristics in our platform. We used this model to unravel maternal pregestational diabetes-induced congenital heart defects. Together, the 2D cardiac platform offers a unique tool for disease modeling, drug discovery and cardiogenesis studying.