The pericardium forms as a distinct structure during heart formation

The heart integrates diverse cell lineages into a functional unit, including the pericardium, a mesothelial sac that supports heart movement, homeostasis, and immune responses. However, despite its critical roles, the developmental origins of the pericardium remain uncertain due to disparate models. Here, using live imaging, lineage tracking, and single-cell transcriptomics in zebrafish, we find the pericardium forms within the lateral plate mesoderm from dedicated anterior mesothelial progenitors and distinct from the classic heart field. Machine learning-based tracking and transcriptional trajectories uncover how pericardial precursors emerge among a bilateral mesothelial progenitor band to enclose the embryonic heart. This process occurs independently of heart tube formation, with canonical Wnt/β-catenin signaling modulating pericardial cell number and tissue rigidity. We link Wnt antagonist expression found in pediatric dilated cardiomyopathy to increased pericardial stiffness in a neonatal rat model. Our findings conceptually advance our models of heart formation with pericardium formation as a distinct process.