Key result
Retinoic acid drives epicardial lineage commitment, while its absence defaults to a myocardial pathway.
Retinoic acid acts as a critical fate switch at the cardiac mesoderm stage, directing human pluripotent stem cells toward epicardial lineage commitment, while its absence defaults to myocardial development.
RA directs epicardial fate in hPSC models; leaves open in vivo validation and regenerative applications.
The signaling mechanisms and developmental dynamics that govern the divergence of myocardial and epicardial lineages during human heart development remain poorly understood. Here, we developed a human pluripotent stem cell-based cardiac development model and employed time-course single-cell RNA sequencing to delineate cardiac lineage specification trajectories. We identified retinoic acid (RA) as a critical fate switch at the cardiac mesoderm stage. RA instructs epicardial lineage commitment of cardiac mesoderm through a primed-epicardium to proepicardium-like population and finally to epicardium, a process requiring precise BMP modulation. Conversely, RA absence directs cardiac mesoderm along a default myocardial pathway, yielding developing and mature cardiomyocytes. Both trajectories are governed by the hierarchical activation of key transcription factors. Our study integrates signaling and dynamics to elucidate the temporal regulatory network of the RA-BMP axis in human cardiac fate determination. These findings provide fundamental insights into human cardiogenesis and a crucial roadmap for modeling heart disease and advancing regenerative strategies.
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Zhou et al. (2026) studied Human cardiogenesis. Retinoic acid (RA) vs. RA absence was evaluated on Cardiac lineage specification trajectories. Retinoic acid acts as a critical fate switch at the cardiac mesoderm stage, instructing epicardial lineage commitment, whereas its absence directs cells along a default myocardial pathway.