Complexity and plasticity of cardiac cellular composition.

The cellular composition of the heart is highly heterogeneous, plastic and sex-specific according to two papers published in Nature and Cardiovascular Research. These findings have important implications for understanding the developmental origins and functional specialization of the heart and also highlight the importance of considering biological sex in studies examining cardiac physiology, stress responses and therapeutic strategies.

In an article published in Nature, researchers isolated approximately half a million single cells and nuclei from 14 donor human hearts and analysed them using single-cell RNA sequencing, single-nucleus RNA sequencing and multiplex RNA small-molecule fluorescence in situ hybridization.

V. Summersby/Springer Nature Limited

Atrial and ventricular tissues differed in their cellular composition. Atrial tissues contained 30.1% cardiomyocytes, 24.3% fibroblasts, 17.1% mural cells (pericytes and vascular smooth muscle cells), 12.2% endothelial cells and 10.4% immune cells (myeloid and lymphoid cells). By contrast, ventricular tissues contained 49.2% cardiomyocytes, 21.2% mural cells, 15.5% fibroblasts, 7.8% endothelial cells and 5.3% immune cells. Furthermore, atrial and ventricular cardiomyocytes had strikingly distinct transcriptional signatures, indicative of their different developmental origins and electrophysiological, contractile and secretory properties.

In the vascular compartment, 17 distinct cell populations with anatomical and arterio–venous specificities were identified. These included ten populations of endothelial cell, four clusters of pericyte, two groups of vascular smooth muscle cell and a small, distinct population of mesothelial cells.

The researchers also identified 7 populations of cardiac fibroblast, 21 states of cardiac immune cell (8 populations of lymphoid cell and 13 populations of myeloid cell, including multiple macrophage, monocyte and dendritic cell subtypes), 6 clusters of neuronal cell and 3 categories of adipocyte.

The investigators note that the expression levels of ACE2, encoding angiotensin-converting enzyme 2, which is the receptor used by SARS-CoV-2 to infect cells, were highest in pericytes, followed by fibroblasts and lowest in cardiomyocytes (with twofold higher expression in ventricular cardiomyocytes than in atrial cardiomyocytes).

In ventricular tissues, the proportion of cardiomyocytes was higher in women than in men; otherwise, the researchers did not note significant differences in cellular distributions between male and female hearts. However, in another paper published in Cardiovascular Research, Alexander Pinto and colleagues investigated the sex-specific differences in the non-myocyte composition of mouse hearts. The researchers found higher levels of resident mesenchymal cells in female hearts than in male hearts. In addition, female hearts had higher proportions of natural killer cells and T cells, whereas male hearts had higher proportions of total myeloid cells, granulocytes and B cells.

These sex-specific differences develop soon after birth and are controlled by gonadal hormones. Gonadectomy caused rapid changes in cardiac cellular composition in the mice, and many of these changes were reversed by the reintroduction of oestrogen or testosterone to female and male mice, respectively, indicating that the cellular composition of the heart is plastic and is regulated by endocrine factors.

“The heart not only has a diverse array of cells — beyond cardiomyocytes and fibroblasts — but also has a sex-specific profile,” comments Pinto. “However, much biomedical research is calibrated to address disease phenotypes observed in males only. This is concerning, particularly in the context of preclinical drug development and testing,” he cautions.