Our analyses of approximately half a million single cells and nuclei from six distinct cardiac regions from fourteen donors considerably expand an emerging reference adult heart cell atlas. By combining single-cell and single-nuclear RNA-seq data with machine learning and in situ imaging techniques, we provide detailed insights across the repertoire of cardiac cells, including cardiomyocytes (excluded by single-cell RNA-seq) and ECs (underrepresented in cardiac snRNA-seq). We quantify the cellular composition highlighting chamber-specific features and differences between male and female donors. Within each cell compartment, we identify and validate prototypic lineage-specific genes, and genes with previously unknown cardiac expression. Our results begin to unravel the molecular underpinnings of cardiac physiology and the cellular response to stress and disease. Cardiomyocytes are the most prevalent cardiac cells and comprise higher percentages in ventricles than atria, and in female versus male ventricular tissues. Transcriptional differences between atrial and ventricular cardiomyocyte populations indicate different developmental origins, distinctive haemodynamic forces and specialized functions in cardiac chambers. Cellular diversity of FBs reveals ECM-producing and ECM-organizing activities that with other cells support cardiomyocytes across varying biophysical stimuli. The vascular compartment contains several ECs and pericyte populations and two SMC subtypes with distinct anatomical and arterio-vascular characteristics. Arterial and venous ECs are predicted to interact with mural cells via Notch signalling pathways involved in regulating vascular homeostasis and development. Immune cells interact with FBs and cardiomyocytes. In addition to confirming previous findings65,66, we show macrophage complexity and infer paracrine circuits for cardiac homeostasis. Cross-tissue analyses delineate cardiac populations distinct from skeletal muscle and kidney. We illustrate the relevance of cardiac cell atlas by defining cell lineages enriched in cardiovascular GWAS and molecules involved in SARS-CoV-2 infection. High expression of the viral receptor ACE2 in pericytes and its correlation with AGTR1 is consistent with the role of renin–angiotensin–aldosterone system signalling in cardiac haemodynamics67. We recognize limitations associated with cell capture by different data sources and unintended bias from surgical sampling. However, we expect our results will inform studies of other cardiac regions (valves, papillary muscle and conduction system), propel studies with large cohorts to determine the roles of age, gender and ancestry on normal cardiac physiology and provide crucial insights to enable mechanistic understanding of heart disease.
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