Abstract
The epicardium is a mesothelial layer covering the myocardium serving as a progenitor source during cardiac development. The epicardium reactivates upon cardiac injury supporting cardiac repair and regeneration. Fine-tuned balanced signaling regulates cell plasticity and cell-fate decisions of epicardial-derived cells (EPCDs) via epicardial-to-mesenchymal transition (EMT). However, powerful tools to investigate epicardial function, including markers with pivotal roles in developmental signaling, are still lacking. Here, we recapitulated epicardiogenesis using human induced pluripotent stem cells (hiPSCs) and identified type II classical cadherin CDH18 as a biomarker defining lineage specification in human active 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 highlight the importance of tracing CDH18 expression in hiPSC-derived epicardial cells, providing a model for investigating epicardial function in human development and disease and enabling new possibilities for regenerative medicine.
Highlights
Cardiovascular diseases are the leading cause of death worldwide
We modified previously reported induction methods for human induced pluripotent stem cells (hiPSCs)-derived epicardial-like (EPI) cells[28,32,35] to robustly yield Wilms’ tumor 1 (WT1)+ cells at a higher rate, and longterm culture of cells was achieved by permanent inhibition of transforming growth factor (TGF)-β (Fig. 2a)
In agreement with previous models, cells did not upregulate aldehyde dehydrogenase 1 member A2 (ALDH1A2)—a gene highly expressed in the epicardium but not PE—until d24, indicating that the cells at d12 represented an early stage during development comparable to PE cells and specified into later stage epicardium at d24 (Fig. 2c, d)
Summary
Cardiovascular diseases are the leading cause of death worldwide. The human heart is incapable of restoring itself and myocardial repair and regeneration processes are still poorly understood. The epicardium re-activates and contributes as a quick transient progenitor hub of derivative cells to the cardiovascular system regeneration[4,12]. This fact provides the epicardium with a pivotal role in mediating regenerative responses. Despite ongoing investigation on the epicardium as a therapeutic target tissue, processes governing epicardial development, reactivation and engraftment ability are not well understood, mainly due to lacking comprehension of the fundamental biology behind the epicardium itself, including the expression dynamics of epicardial epitopes mediating tissue responses to homeostasis disruptions and cellular signaling upon cardiac damage. Cell-surface markers defining functional epicardial cells or regulating epicardial cellfate decisions have been difficult to identify
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