MSGID: 1:317/3 64af7dfd   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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   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/   
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   provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited   
   for style and length.   
      
      
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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   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230712124621.htm   
      
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