Single-cell atlas of the Wuzhishan miniature pig heart identifies a species-specific lipid-metabolic cardiomyocyte subpopulation

The Wuzhishan miniature pig is regarded as a highly promising translational model for cardiac xenotransplantation due to its close physiological resemblance to humans. However, a comprehensive single-cell atlas systematically delineating the postnatal developmental dynamics of its heart has been lacking. In this study, we constructed the first high-resolution integrated single-cell and single-nucleus transcriptomic atlas of the Wuzhishan miniature pig heart, spanning five critical developmental stages from neonatal to adult. We systematically characterized the cellular panorama and dynamic landscape of postnatal cardiac maturation, and uncovered the remodeling of intercellular communication networks during heart development. Through cross-species comparative analysis, we identified a unique ventricular cardiomyocyte subpopulation with highly active lipid metabolism (VCM-LM-SR) specific to the Wuzhishan miniature pig. This subpopulation not only exhibits highly active lipid metabolism but also occupies a hub position in the adult cardiac cellular interactome. Further analysis revealed that the activity of multiple human cardiac disease-related pathways is significantly lower in cardiomyocytes of the Wuzhishan miniature pig compared to other species examined, indicating a distinct transcriptional baseline in this donor animal. In summary, this atlas not only elucidates the cellular and molecular dynamics of cardiac development in the Wuzhishan miniature pig but also, through cross-species analysis, reveals a species-specific metabolic adaptation phenotype in this breed. These findings provide a novel perspective and a foundational resource for studying human cardiac metabolism using large animal models.