CDH18 is an epicardial biomarker regulating epicardial specification and differentiation towards vascular smooth muscle cells

The epicardium is a mesothelial layer covering the myocardium and contributes to different cardiac lineage descendants during cardiogenesis. Fine-tuned balanced signaling defines epicardial specification and regulates cell plasticity and cell-fate decisions of epicardial-derived cells (EPCDs) by epicardial-to-mesenchymal transition (EMT). However, powerful tools to investigate epicardial cell function, including markers with pivotal roles in developmental signaling, are still lacking. Here, we recapitulated embryonic epicardiogenesis using human induced pluripotent stem cells (hiPSCs) and identified type II classical cadherin CDH18 as a novel biomarker defining lineage specification in human developing epicardium. The loss of CDH18 led to the onset of EMT and specific differentiation towards cardiac smooth muscle cells. Furthermore, GATA4 regulated epicardial CDH18 expression. These results demonstrate the production and enrichment of hiPSC-derived epicardial cells via the tracing of CDH18 expression, providing a model for investigating epicardial function in human development and disease and enabling new possibilities for regenerative medicine. Overall design: human induced pluripotent stem cells (hiPSCs) were differentiated into EPI cells (hiPSC-EPI). On day 12 and 24, cells were treated to undergo EMT towards smooth muscle cells (iSMC) and cardiac fibroblast (iCF). hiPSC-EPI were also transfected with a siRNA against CDH18 to evaluate the causal role in the loss of function