The heterocellular heart: identities, interactions, and implications for cardiology

Fig. 1. The heterocellular heart. A Number of publications per year included in PubMed between 1945 and 2021 that refer to the heart and one of the specified cell types in the title or abstract, compared to publications that refer to the heart only (divided by a factor of 50 for better visibility). B Uniform manifold approximation and projection (UMAP) of 11 cell types of the adult human heart as identified by scRNA-seq (from [102] under Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/)

Fig. 2. Heterocellular interactions in the healthy heart. Cell communication in the heart involves ‘biochemical’ and ‘biophysical’ cues. Secreted factors that act in a paracrine or autocrine manner include cytokines, chemokines, or growth factors. These factors may be secreted to the extracellular space, ‘wrapped up’ in exosomes, be transported via tunnelling nanotubes, etc. In addition, metabolites may act as signalling molecules. Cardiac cells are responsive to endocrine factors and neurotransmitters that may derive from the circulation or intracardiac nerve endings. Biophysical interactions involve direct mechanical cell–cell coupling via adherens junctions or tight junctions, as well as indirect mechanical coupling such as via extracellular matrix/integrins connections. Electrical coupling in the heart typically involves connexins, a class of transmembrane proteins that forms gap junctions between cells

Fig. 3. Gene expression in heart tissue compared to cardiac cells. A Cellular mRNA content is approximately linearly correlated with cell volume. B As cardiomyocytes are large cells that, in contrast to their numerical share, account for most of the total cardiac cell volume, they dominate mRNA expression in heart tissue. Conversely, mRNA from smaller and/or less abundant cell types is underrepresented in cardiac tissue mRNA pool analyses. C mRNA expression (fragments per kilobase of transcript per million mapped reads) in isolated cardiac cells, compared to whole heart tissue (modified from [106] with permission)

Fig. 4. Implications for therapeutic interventions. A Biochemical cell–cell interactions via secreted molecules can be inhibited by therapeutic antibodies or receptor blockers. B Chemical properties influence tissue and cell distribution of therapeutic drugs. C Targeting carriers such as antibody–drug conjugates or nanoparticles with or without modified surface antigens can steer drug delivery towards certain cell types. D Antisense therapeutics and viral vectors enable gene silencing, overexpression, and DNA editing in cardiac cells. E Chimeric antigen receptor (CAR) T cells directed against a specific target cell type can be obtained by genetic engineering. F Pathological gene expression can be inhibited by epigenetic drugs or modulators of protein–protein interaction (PPI)