Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy

Mark Chaffin, Irinna Papangeli, Bridget Simonson, Amer-Denis Akkad, Matthew C. Hill, Alessandro Arduini, Stephen J. Fleming, Michelle Melanson, Sikander Hayat, Maria Kost-Alimova, Ondine Atwa, Jiangchuan Ye, Kenneth C. Bedi, Matthias Nahrendorf, Virendar K. Kaushik, Christian M. Stegmann, Kenneth B. Margulies, Nathan R. Tucker and Patrick T. Ellinor ()
Additional contact information
Mark Chaffin: The Broad Institute
Irinna Papangeli: Bayer US LLC
Bridget Simonson: The Broad Institute
Amer-Denis Akkad: Bayer US LLC
Matthew C. Hill: The Broad Institute
Alessandro Arduini: The Broad Institute
Stephen J. Fleming: The Broad Institute
Michelle Melanson: The Broad Institute
Sikander Hayat: Bayer US LLC
Maria Kost-Alimova: The Broad Institute
Ondine Atwa: The Broad Institute
Jiangchuan Ye: The Broad Institute
Kenneth C. Bedi: University of Pennsylvania
Matthias Nahrendorf: Massachusetts General Hospital
Virendar K. Kaushik: The Broad Institute
Christian M. Stegmann: Bayer US LLC
Kenneth B. Margulies: University of Pennsylvania
Nathan R. Tucker: Masonic Medical Research Institute
Patrick T. Ellinor: The Broad Institute

Nature, 2022, vol. 608, issue 7921, 174-180

Abstract: Abstract Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function1,2 and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts3,4, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGFβ1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.

Date: 2022
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DOI: 10.1038/s41586-022-04817-8

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