Kazumasa Kanemaru, James Cranley, Daniele Muraro, Antonio M.A. Miranda, Jan Patrick Pett, Monika Litvinukova, Natsuhiko Kumasaka, Siew Yen Ho, Krzysztof Polanski, Laura Richardson, Lukas Mach, Monika Dabrowska, Nathan Richoz, Sam N. Barnett, Shani Perera, Anna Wilbrey-Clark, Carlos Talavera-López, Ilaria Mulas, Krishnaa T. Mahbubani, Liam Bolt, Lira Mamanova, Liz Tuck, Lu Wang, Margaret M. Huang, Martin Prete, Sophie Pritchard, John Dark, Kourosh Saeb-Parsy, Minal Patel, Menna R. Clatworthy, Norbert Hübner, Rasheda A. Chowdhury, Michela Noseda, and Sarah A. Teichmann
A cell’s function is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here, we combine single-cell and spatial transcriptomic data to discover cellular niches within eight regions of the human heart. We map cells to micro-anatomic locations and integrate knowledge-based and unsupervised structural annotations. For the first time, we profile the cells of the human cardiac conduction system, revealing their distinctive repertoire of ion channels, G-protein coupled receptors, and cell interactions using a customCellPhoneDB.orgmodule. We show that the sinoatrial node is compartmentalised, with a core of pacemaker cells, fibroblasts and glial cells supporting paracrine glutamatergic signalling. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions, providing unexpected 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 which may contribute to infection defence. We define a ventricular myocardial-stress niche enriched for activated fibroblasts and stressed cardiomyocytes, cell states that are expanded in cardiomyopathies. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be deployed to other tissues and organs.