Journal Article

Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy

Tucker, Nathan R., Bedi, Kenneth C., Hill, Matthew C., Arduini, Alessandro, Fleming, Stephen J., Chaffin, Mark, Papangeli, Irinna, Simonson, Bridget, Hayat, Sikander, Kaushik, Virendar K., Stegmann, Christian M., Nahrendorf, Matthias, Margulies, Kenneth B., Melanson, Michelle, Akkad, Amer-Denis, Atwa, Ondine, Ellinor, Patrick T., Kost-Alimova, Maria, Ye, Jiangchuan

2022

Overview

Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function 1 , 2 and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts 3 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14/32 / 38 / 38/39 / 38/91 / 631/208/199 / 631/337/2019 / 692/699/75/74 / Biomarkers / Cardiomyocytes / Cardiomyopathy / Cardiomyopathy, Dilated - genetics / Cardiomyopathy, Dilated - pathology / Cardiomyopathy, Hypertrophic - genetics / Cardiomyopathy, Hypertrophic - pathology / Case-Control Studies / Cell cycle / Cell Nucleus - genetics / Cells, Cultured / Congestive heart failure / Convergence / Coronary artery disease / CRISPR / CRISPR-Cas Systems / Dilated cardiomyopathy / Fibroblasts / Gene expression / Gene Expression Profiling / Gene Knockout Techniques / Gene sequencing / Genes / Heart diseases / Heart failure / Heart Failure - genetics / Heart Failure - pathology / Heart Ventricles - metabolism / Heart Ventricles - pathology / Humanities and Social Sciences / Humans / Lymphocytes / multidisciplinary / Muscle contraction / Mutation / Myocardium - metabolism / Myocardium - pathology / Myofibroblasts - metabolism / Myofibroblasts - pathology / Neutrophils / Nuclei / Nuclei (cytology) / Public health / RNA-Seq / Science / Science (multidisciplinary) / Single-Cell Analysis / Therapeutic targets / Transcription / Transcription, Genetic / Transforming Growth Factor beta1 / Ventricle