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Human Heart Cell Atlas Highlights Cardiac Functions, Drug Targets

NEW YORK – An international team of researchers has put together an atlas of the human heart that spells out transcriptomic and chromatin accessibility features in individual, spatially mapped cells across eight distinct areas.

"In this study, we charted eight regions of the human heart and provided the most detailed and comprehensive human Heart Cell Atlas to date," James Cranley, a graduate student, cardiologist, and heart rhythm disorder specialist at the Wellcome Sanger Institute, said in an email. "Specifically, we described several novel cell types, including the cells of the cardiac conduction system, which had not been profiled at single-cell resolution in humans before."

As they reported in Nature on Wednesday, Cranley and colleagues performed single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC-seq-based chromatin accessibility profiling on hundreds of thousands of cells, combining these data with 10x Genomics-based spatial transcriptomic profiles as well as tissue section annotation by cardiac anatomy experts.

The team also brought in published single-cell RNA-seq and snRNA-seq data to get a glimpse at the precise locations of specific cell types in the heart, along with their functions and regulatory features.

"This framework, which combined multimodal data and integrated knowledge-based and unsupervised microstructural annotations, has the power to drive niche discovery and can be applied to other tissues in health and disease," the authors wrote.

With the help of unbiased computational strategies, the researchers were able to characterize cell types and gene expression profiles in the heart's left ventricle, right ventricle, left atria, right atria, apex, interventricular septum, sinoatrial node, and atrioventricular node.

Their analyses highlighted dozens of cardiac cell states — a set that encompassed an immune microenvironment niche and a myocardial stress niche, as well as the cellular components behind the heart's signature beat, particularly its electrical "cardiac conduction system."

"This Heart Cell Atlas reveals cardiac microanatomy in unprecedented detail, including the cardiac conduction system that enables each heartbeat, and is a valuable reference for studying heart disease and designing potential therapeutics," co-senior and co-corresponding author Sarah Teichmann, a researcher affiliated with the Wellcome Sanger Institute and Imperial College London's National Heart and Lung Institute, said in a statement.

In particular, the researchers got a detailed look at the suite of pacemaker, fibroblast, and glial cells found in the sinoatrial node, a region linked to the heart's natural pacemaker activity. There, they distinguished between a core sinoatrial node region comprised of glial cell-surrounded pacemaker cells and a more peripheral sinoatrial node defined by distinct gene expression patterns.

By combining the expression and chromatin accessibility patterns present in different cardiac cell types with insights on genetic risk variants implicated in heart disease, meanwhile, the team unearthed the specific cell types that are most likely affected in such conditions.

To complement the datasets developed for the study, the researchers also came up with a set of related computational methods, including a drug2cell tool for predicting potential drug targets or interactions between drugs and biological targets.

"Off-target activity of non-cardiac therapies on the heart and its conduction system is a major reason for drug development failure and withdrawal," the authors explained. "To help address this challenge, we develop a pipeline, drug2cell, which integrates drug-target interactions from the [European Molecular Biology Laboratory's] ChEMBL database with user-provided data to comprehensively evaluate drug-target expression in single cells."

When the team applied the drug2cell approach to pacemaker cell data, for example, it tracked down cells expressing a target for so-called GLP-1 analogs that are used to treat conditions such as diabetes or epilepsy. These predictions, coupled with follow-up experiments in pacemaker-like cardiomyocyte cell models, suggested that inadvertent pacemaker cell targeting may contribute to the heart rate changes described in individuals taking such drugs.

The study is one component of the Human Cell Atlas (HCA) effort, which aims to understand the functions of individual cells across human tissues, organs, and systems, the researchers explained, noting that "our suite of computational approaches can be applied to other tissues and organs."

"This framework, which combined multimodal data and integrated knowledge-based and unsupervised microstructural annotations, has the power to drive niche discovery and can be applied to other tissues in health and disease," the authors wrote.