Spatially resolved multiomics of human cardiac niches

Kanemaru, K.; Cranley, J.; Muraro, D.; Miranda, A. M. A.; Pett, J. P.; Litvinukova, M.; Kumasaka, N.; Ho, S. Y.; Polanski, K.; Richardson, L.; Mach, L.; Dabrowska, M.; Richoz, N.; Barnett, S. N.; Perera, S.; Wilbrey-Clark, A. L.; Talavera-Lopez, C.; Mulas, I.; Mahbubani, K. T.; Bolt, L.; Mamanova, L.; Tuck, L.; Wang, L.; Huang, M. M.; Prete, M.; Pritchard, S.; Dark, J.; Saeb-Parsy, K.; Patel, M.; Clatworthy, M. R.; Chowdhury, R. A.; Noseda, M.; Teichmann, S. A.

doi:10.1101/2023.01.30.526202

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bioRxiv · 10.1101/2023.01.30.526202

Spatially resolved multiomics of human cardiac niches

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Abstract

A cells 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 custom CellPhoneDB.org module. 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.

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Kanemaru, K., Cranley, J., Muraro, D., Miranda, A. M. A., Pett, J. P., Litvinukova, M., Kumasaka, N., Ho, S. Y., Polanski, K., Richardson, L., Mach, L., Dabrowska, M., Richoz, N., Barnett, S. N., Perera, S., Wilbrey-Clark, A. L., Talavera-Lopez, C., Mulas, I., Mahbubani, K. T., Bolt, L., Mamanova, L., Tuck, L., Wang, L., Huang, M. M., Prete, M., Pritchard, S., Dark, J., Saeb-Parsy, K., Patel, M., Clatworthy, M. R., Chowdhury, R. A., Noseda, M., Teichmann, S. A.. 2023-02-01. Spatially resolved multiomics of human cardiac niches. https://doi.org/10.1101/2023.01.30.526202

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