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Spatially resolved multiomics of human cardiac niches

Lookup NU author(s): Dr Lu Wang, Professor John Dark

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2023, The Author(s).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.


Publication metadata

Author(s): Kanemaru K, Cranley J, Muraro D, Miranda AMA, Ho SY, Wilbrey-Clark A, Patrick Pett J, Polanski K, Richardson L, Litvinukova M, Kumasaka N, Qin Y, Jablonska Z, Semprich CI, Mach L, Dabrowska M, Richoz N, Bolt L, Mamanova L, Kapuge R, Barnett SN, Perera S, Talavera-Lopez C, Mulas I, Mahbubani KT, Tuck L, Wang L, Huang MM, Prete M, Pritchard S, Dark J, Saeb-Parsy K, Patel M, Clatworthy MR, Hubner N, Chowdhury RA, Noseda M, Teichmann SA

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2023

Volume: 619

Pages: 801-810

Online publication date: 12/07/2023

Acceptance date: 12/06/2023

Date deposited: 07/08/2023

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Research

URL: https://doi.org/10.1038/s41586-023-06311-1

DOI: 10.1038/s41586-023-06311-1


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Funding

Funder referenceFunder name
2019-002431
2019-202666
a British Heart Foundation PhD studentship
a China Scholarship Council–Imperial PhD studentship
a National Heart and Lung Institute PhD studentship
16CVD03
2021-237882
a British Society for Heart Failure Research Fellowship
AdG788970
Alexander Jansons Myocarditis UK
FS/CRTF/23/24444
NIHR203332
SFB-1470–B03
the NIHR Imperial Biomedical Research Centre (BRC)
SP/19/1/34461
the National Institute for Health and Care Research (NIHR) Blood and Transplant Research Unit in Organ Donation and Transplantation
the Overseas Research Fellowship of the Takeda Science Foundation
the Wellcome Trust Clinical PhD Fellowship
WT206194

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