Spatially resolved multiomics of human cardiac niches

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system(1). The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG(+) and IgA(+) plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.

Automated summary

In this study, single-cell and spatial transcriptomics data were used to explore cellular niches in eight regions of the human heart. Specific ion channels, G-protein-coupled receptors, and regulatory networks were identified in different cell types, highlighting the importance of FOXP2 in pacemaker cells. The sinoatrial node was found to be compartmentalized, with glial cells and fibroblasts supporting glutamatergic signaling. The study also introduced a drug target prediction tool, drug2cell, and revealed the presence of immune niches in the epicardium.