Detailed map of the heart provides new insights into cardiac health and disease

Date:
July 12, 2023
Source:
Wellcome Trust Sanger Institute
Summary:
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.


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FULL STORY ==========================================================================
In a new study, published today (12 July) in Nature, researchers have
produced the most detailed and comprehensive human Heart Cell Atlas to
date, including the specialised tissue of the cardiac conduction system -- where the heartbeat originates.

The multi-centre team is led by the Wellcome Sanger Institute and the
National Heart and Lung Institute at Imperial College London, and has
also presented a new drug-repurposing computational tool called Drug2cell, which can provide insights into the effects of drugs on heart rate.

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 --
the group of cells responsible for the heartbeat -- not understood at
such a detailed level (1) in humans before. The human cardiac conduction system, the heart's 'wiring', sends electrical impulses from the top to
the bottom of the heart and coordinates the heartbeat.

By using spatial transcriptomics, which gives a "map" of where cells
sit within a tissue, researchers were also able to understand how these
cells communicate with each other for the first time. This map acts as a molecular guidebook, showing what healthy cells look like, and providing
a crucial reference to understand what goes wrong in disease. The findings
will help 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. Around 20,000
electronic pacemakers are implanted each year in the UK for these
disorders (2). These can be ineffective and are prone to complications
and side-effects (3).

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 team also 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.

Dr James Cranley, joint first author, a cardiologist specialising in
heart rhythm disorders and PhD student at the Wellcome Sanger Institute,
said: "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. 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." Dr Kazumasa Kanemaru, joint first author and Postdoctoral Fellow in the Gene Expression Genomics team at the Wellcome
Sanger Institute, said: "The mechanism of activating and suppressing
pacemaker cell genes is not clear, especially in humans. 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
(4) that could be interpreted as an early warning sign of heart failure.

Dr Michela Noseda, senior Lecturer in Cardiac Molecular Pathology
at the National Heart and Lung Institute, Imperial College London,
a Coordinator of the Human Cell Atlas Heart BioNetwork and a lead
author, said: "We often don't fully know what impact a new treatment
will have on the heart and its electrical impulses -- this can mean a
drug is withdrawn or fails to make it to the market. Our team developed
the Drug2cell platform to improve how we evaluate new treatments and how
they can affect our hearts, and potentially other tissues too. This could provide us with an invaluable tool to identify new drugs which target
specific cells, as well as help to predict any potential side-effects
early on in drug development." Professor Metin Avkiran, Associate
Medical Director at the British Heart Foundation, which part-funded the research with the German Centre for Cardiovascular Research (DZHK), said: "Using cutting-edge technologies, this research provides further intricate detail about the cells that make up specialised regions of the human heart
and how those cells communicate with each other. The new findings on the heart's electrical conduction system and its regulation are likely to open
up new approaches to preventing and treating rhythm disturbances that
can impair the heart's function and may even become life-threatening." "International collaboration is key to scientific progress. This impactful study and other discoveries from the broader Human Cell Atlas initiative
are excellent examples of what can be achieved when the international
research community works together across borders. Our combined efforts
can ultimately produce better outcomes for patients worldwide." Dr Sarah Teichmann, a senior author of the study from the Wellcome Sanger Institute
and co-chair of the Human Cell Atlas Organising Committee, said: "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. An important contribution to the global Human
Cell Atlas initiative, which is mapping every cell type in the body
to understand health and disease, it will form the foundation for a
fully integrated HCA Human Heart Cell Atlas. In addition, our suite of computational methods will help identify possibilities for repurposing
existing drugs to treat diseases in other tissues." More information
can be found at https://www.humancellatlas.org/
* RELATED_TOPICS
o Health_&_Medicine
# Heart_Disease # Stem_Cells # Diseases_and_Conditions #
Lymphoma # Immune_System # Vioxx # Stroke_Prevention #
Lung_Cancer
* RELATED_TERMS
o Defibrillation o Hormone o Artificial_heart o Stem_cell
o Heart_rate o Heart_failure o Stem_cell_treatments o
Electrocardiogram

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========================================================================== Journal Reference:
1. Kazumasa Kanemaru, James Cranley, Daniele Muraro, Antonio
M. A. Miranda,
Siew Yen Ho, Anna Wilbrey-Clark, Jan Patrick Pett, Krzysztof
Polanski, Laura Richardson, Monika Litvinukova, Natsuhiko Kumasaka,
Yue Qin, Zuzanna Jablonska, Claudia I. Semprich, Lukas Mach, Monika
Dabrowska, Nathan Richoz, Liam Bolt, Lira Mamanova, Rakeshlal
Kapuge, Sam N.

Barnett, Shani Perera, Carlos Talavera-Lo'pez, Ilaria Mulas,
Krishnaa T.

Mahbubani, Liz Tuck, Lu Wang, Margaret M. Huang, Martin Prete,
Sophie Pritchard, John Dark, Kourosh Saeb-Parsy, Minal Patel,
Menna R.

Clatworthy, Norbert Hu"bner, Rasheda A. Chowdhury, Michela Noseda,
Sarah A. Teichmann. Spatially resolved multiomics of human cardiac
niches.

Nature, 2023; DOI: 10.1038/s41586-023-06311-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230712124621.htm

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