Single-cell transcriptomics uncovers conserved cardiac cell types and regulatory adaptation across birds and mammals

Abstract

Birds and mammals possess highly efficient four-chambered hearts to meet the elevated metabolic demands of endothermy, yet the cellular and molecular basis of this convergent evolution remains poorly understood. To address this gap, we generated the first single-cell heart transcriptomic atlas of a wild bird, the Eurasian Tree Sparrow (Passer montanus), across neonatal and adult stages, and integrated it with existing human and mouse data. This cross-species comparison reveals broadly conserved transcriptional profiles: cardiomyocytes are the most transcriptionally conserved cell type across species and developmental stages, whereas non-myocyte populations (fibroblasts and endothelial cells) show greater transcriptional plasticity. These findings suggest that cardiac diversification and adaptation may occur primarily through regulatory changes within a shared cellular repertoire. Extending this framework, we investigate cardiac adaptation to high-elevation hypoxia in tree sparrows. Strikingly, the transcriptional programs significantly overlapped with genes previously linked to cardiac remodeling and disease-related phenotypes in humans and mice. To test the functional relevance of this overlap, we performed in vitro assays and found that IGF1R overexpression drives hypertrophy-like growth in avian cardiomyocytes, accompanied by PI3K-AKT-mTOR-associated transcriptional reprogramming, a pathway critically implicated in mammalian cardiac hypertrophy. Collectively, our findings demonstrate that birds and mammals share a conserved cardiac cellular blueprint, wherein regulatory programs are recurrently co-opted during development, adaptation to hypoxia, and pathological remodeling.