A human cell atlas of the pressure-induced hypertrophic heart
Luka Nicin, Sam Michael Schroeter, Simone-Franziska Glaser, Ralf Schulze-Brüning, Minh Duc Pham, Susanne Hille, Michail Yekelchyk, Badder Kattih, Wesley Abplanalp, Lukas Tombor, Oliver J. Müller, Thomas Braun, Benjamin Meder, Christoph Reich, Mani Arsalan, Tomáš Holubec, Thomas Walther, Fabian Emrich, Jaya Krishnan, Andreas M. Zeiher, David John, Stefanie Dimmeler
Abstract
Pathological cardiac hypertrophy is a leading cause of heart failure, but knowledge of the full repertoire of cardiac cells and their gene expression profiles in the human hypertrophic heart is missing. Here, by using large-scale single-nucleus transcriptomics, we present the transcriptional response of human cardiomyocytes to pressure overload caused by aortic valve stenosis and describe major alterations in cardiac cellular crosstalk. Hypertrophied cardiomyocytes had reduced input from endothelial cells and fibroblasts. Genes encoding Eph receptor tyrosine kinases, particularly EPHB1, were significantly downregulated in cardiomyocytes of the hypertrophied heart. Consequently, EPHB1 activation by its ligand ephrin (EFN)B2, which is mainly expressed by endothelial cells, was reduced. EFNB2 inhibited cardiomyocyte hypertrophy in vitro, while silencing its expression in endothelial cells induced hypertrophy in co-cultured cardiomyocytes. Our human cell atlas of the hypertrophied heart highlights the importance of intercellular crosstalk in disease pathogenesis and provides a valuable resource.