Abstract
The vertebrate heart is composed of heterogeneous cardiomyocyte (CM) populations, however, the roles of distinct CM subpopulations in heart development and repair remain poorly defined. Here, using single-cell RNA sequencing analysis of adult zebrafish heart, we identified a unique CM subpopulation marked by the expression of phlda2, which is associated with anaerobic metabolism and different from mature CMs that are enriched for oxidative phosphorylation genes. We demonstrated phlda2 (+) cells constituted a primordial CM compartment localized between compact and trabecular muscles. Genetic ablation of phlda2 (+) CMs during development severely disrupted heart morphogenesis, leading to defective myocardial trabeculation and compaction, and impaired coronary vascularization. Surprisingly, despite their essential roles in development, the depletion of phlda2 (+) CMs didn't impair myocardial restoration and revascularization following ventricular resection. We further found that primordial CMs failed to regenerate after either surgical amputation or genetic ablation, indicating a limited regenerative capacity. Our findings identify primordial CMs as an organizer for heart morphogenesis but not essential for regeneration, revealing a fundamental difference between developmental and regenerative programs in the vertebrate heart.