Researchers have produced the most detailed and comprehensive human heart cell atlas to date, including the specialized tissue of the cardiac conduction system—where the heartbeat originates. The team has also presented a new drug-repurposing computational tool called Drug2cell, which can provide insights into the effects of drugs on heart rate.

This work is published in Nature, in the paper, “Spatially resolved multiomics of human cardiac niches.

This study is part of the international Human Cell Atlas (HCA) initiative, which is mapping every cell type in the human body, to transform our understanding of health and disease, and will form the foundation for a fully integrated HCA Human Heart Cell Atlas.

Charting eight regions of the human heart, the work describes 75 different cell states including the cells of the cardiac conduction system—not understood at such a detailed level in humans before. The human cardiac conduction system sends electrical impulses from the top to the bottom of the heart and coordinates the heartbeat.

“The cardiac conduction system is critical for the regular and coordinated beating of our hearts, yet the cells which make it up are poorly understood,” noted James Cranley, MD, a cardiologist specializing in heart rhythm disorders and a PhD student at the Wellcome Sanger Institute. “This study sheds new light by defining the profiles of these cells, as well as the multicellular niches they inhabit. This deeper understanding opens the door to better, targeted anti-arrhythmic therapies in the future.”

By using spatial transcriptomics, researchers were also able to understand how these cells communicate with each other for the first time. The findings will help us understand diseases such as those affecting the heart rhythm.

The assembly of a Human Heart Cell Atlas is key given that cardiovascular diseases are the leading cause of death globally. Understanding the biology of the cells of the conduction system and how they differ from muscle cells paves the way to therapies to boost cardiac health and develop targeted treatments for arrhythmias.

“The mechanism of activating and suppressing pacemaker cell genes is not clear, especially in humans,” noted Kazumasa Kanemaru, PhD, a postdoctoral fellow in the gene expression genomics team at the Wellcome Sanger Institute. “This is important for improving cell therapy to facilitate the production of pacemaker cells or to prevent the excessive spontaneous firing of cells. By understanding these cells at an individual genetic level, we can potentially develop new ways to improve heart treatments.”

The study unearthed an unexpected discovery: a close relationship between conduction system cells and glial cells. Glial cells are part of the nervous system and are traditionally found in the brain. They have been explored very little in the heart. This research suggests that glial cells are in physical contact with conduction system cells and may play an important supporting role: communicating with the pacemaker cells, guiding nerve endings to them, and supporting their release of glutamate, a neurotransmitter.

Another key finding of the study is an immune structure on the heart’s outer surface. This contains plasma cells, which release antibodies into the space around the heart to prevent infection from the nearby lungs. The researchers also identified a cellular niche enriching for a hormone that could be interpreted as an early warning sign of heart failure.

In addition, the team presents a new computational tool called Drug2cell. The tool can predict drug targets as well as drug side effects. It leverages single-cell profiles and the 19 million drug-target interactions in the EMBL-EBI ChEMBL database.

Unexpectedly, this tool identified that pacemaker cells express the target of certain medications, such as GLP1 drugs, which are used for diabetes and weight loss and are known to increase the heart rate as a side-effect, the mechanism of which was unclear. This study suggests that the increase in heart rate might be partly due to a direct action of these drugs on pacemaker cells, a finding the team also showed in an experimental stem cell model of pacemaker cells.

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