Transcriptional and Cellular Diversity of the Human Heart
- 14 May 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 142 (5), 466-482
- https://doi.org/10.1161/circulationaha.119.045401
Abstract
Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular transcriptomes at single cell resolution at scale, here we have applied these approaches to assess the cellular and transcriptional diversity of the non-failing human heart. Methods: Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from seven human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based upon transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data. Results: We sequenced the transcriptomes of 287,269 single cardiac nuclei, revealing a total of 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblasts subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Finally, intersection of our dataset with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity. Conclusions: Using large-scale single nuclei RNA sequencing, we have defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.This publication has 64 references indexed in Scilit:
- The UCSC genome browser and associated toolsBriefings in Bioinformatics, 2012
- Standardizing predictive values in diagnostic imaging researchJournal of Magnetic Resonance Imaging, 2011
- Induction of sodium channel Nax (SCN7A) expression in rat and human hippocampus in temporal lobe epilepsyEpilepsia, 2010
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic CardiomyopathyJournal of the American College of Cardiology, 2009
- Variants conferring risk of atrial fibrillation on chromosome 4q25Nature, 2007
- Substrate specificity of the human UDP‐glucuronosyltransferase UGT2B4 and UGT2B7The FEBS Journal, 2007
- Using GOstats to test gene lists for GO term associationBioinformatics, 2006
- The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic heartsCardiovascular Pathology, 2004
- TTD: Therapeutic Target DatabaseNucleic Acids Research, 2002