Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w

Single nuclei sequencing reveals novel insights into the regulation of cellular signatures in children with dilated cardiomyopathy

L. Nicin1, W. Abplanalp2, A. Schänzer3, A. Sprengel4, D. John1, H. Mellentin1, L. Tombor2, M. Keuper3, E. Ullrich5, K. Klingel6, R. Dettmeyer3, J. Hoffmann7, H. Akintuerk4, C. Jux4, D. Schranz8, A. M. Zeiher7, S. Rupp4, S. Dimmeler9, für die Studiengruppe: DZHK

1Institute for Cardiovascular Regeneration, Goethe Universität Frankfurt am Main, Frankfurt am Main; 2Institute of Cardiovascular Regeneration and Department of Cardiology, Goethe Universität Frankfurt am Main, Frankfurt am Main; 3Universitätsklinikum Gießen und Marburg GmbH, Gießen; 4Klinik für Kinderkardiologie, Kinderherzzentrum, Universitätsklinikum Gießen und Marburg GmbH, Gießen; 5Universitätsklinikum Frankfurt, Frankfurt am Main; 6Kardiopathologie, Universitätsklinikum Tübingen, Tübingen; 7Med. Klinik III - Kardiologie Zentrum der Inneren Medizin, Universitätsklinikum Frankfurt, Frankfurt am Main; 8Klinik für Kinder u. Jugendmedizin, Universitätsklinikum Frankfurt, Frankfurt am Main; 9Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration, Goethe Universität Frankfurt am Main, Frankfurt am Main;

AIMS: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology and molecular fingerprints into account. We present snRNA-seq from pediatric DCM patients as the next step in identifying cellular signatures. METHODS AND RESULTS: We processed heart tissue from six children with DCM with an age of 0.5, 0.75, 5, 6, 12 and 13 years. Unsupervised clustering of 18,211 nuclei led to the identification of 14 distinct clusters with 6 major cell types. The number of nuclei in fibroblast clusters increased with age in DCM patients, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of DCM patients over 6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms and signatures of fibroblast activation. Additionally, a population of cardiomyocytes with a high pro-regenerative profile was identified in infant DCM patients, but was absent in > 6-year-old children. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes and alterations in ß-adrenergic signaling genes. CONCLUSION: Novel insights into the cellular transcriptomes of hearts from pediatric DCM patients provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched pro-regenerative signatures in infants.

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