Mapping the human heart for the human cell atlas

An international team of researchers are seeking to explore the heart at a depth that was previously impossible.

The Heart Seed Network received a grant of nearly four million US dollars from the Chan Zuckerberg Initiative – as one of the 38 Seed Networks working on the Human Cell Atlas. The National Heart and Lung Institute is delighted that Dr Michela Noseda and Professor Stuart Cook are collaborators on this exciting new initiative.

"This work places NHLI and Imperial in a strategic position within a growing international network" Dr Michela Noseda

At one time or another, everyone discovers that matters of the heart can be quite tricky. But on the other hand, most of us take our heartbeat for granted. “This, however, is where it gets really complicated,” says Professor Norbert Hübner, head of the Genetics and Genomics of Cardiovascular Diseases group at the Max Delbrück Center for Molecular Medicine (MDC). Hübner has assembled a team of thirteen of the world’s leading scientists – from Germany, the United Kingdom, and the United States – dedicated to probing and understanding the human heart, cell by cell. Their project is part of the Human Cell Atlas initiative, for which the Chan Zuckerberg Initiative (CZI) is supporting a total of 38 networks, each focused on different tissues and organs.

Dr Michela Noseda will be working as part of the Heart Seed Network to map the cellular landscape of the heart to generate a reference atlas which will guide subsequent analyses of heart disease and its subtleties.  The exciting new aspect of this research is the desire to reconstruct the anatomy of the heart one cell at the time, using the application of single cell technologies in combination with spatial transcriptomics. The aim of the project is to have a precise understanding of the cellular organisation of the cardiac tissue, with an unprecedented level of detail of the diversity of cell types, the intercellular networks of communication between cells and electrochemical or biophysical signalling mechanisms.

The assembly of a healthy heart atlas is a crucial step towards a completely new vision of the microscopic tissues and cellular demographics of the heart. Paving the way for the expansion of molecular pathology approaches enabling scientists, and eventually clinicians, to discover new ways to diagnose heart conditions, and predict the development of disease, as well as new therapeutic targets within the space of precision medicine. This work places NHLI and Imperial in a strategic position within a growing international network including world-leading research centres such as Harvard University, Max Delbrück Center for Molecular Medicine, Stanford University and the Wellcome Sanger Institute. 

“Working together towards a common goal”

“The global Human Cell Atlas effort is a beacon for what can be accomplished when experts across scientific fields and time zones work together towards a common goal,” says CZI Head of Science Cori Bargmann. The scientists working on the Human Cell Atlas want to further our understanding of the cells in the heart. This includes documenting which genes are currently turned on or turned off, which cell states exist and which cell type is responsible for what, how cells form tissue, and how cells change over their lifetime.

The Seed Network plans to collect samples from ten female and ten male donor hearts, each time from six precisely defined areas, in order to outline the variability of a healthy heart and its cell populations. What differences exist between men and women? Which variations simply show that every human is different, and which indicate that the cells are under stress? “Before we examine unhealthy hearts and can explain why certain heart diseases occur more often in women than in men and vice versa, we need a reference,” says Hübner. “This is similar to the Human Genome Project. Our network is, of course, only taking the first steps, but we can already discern a rough pattern.”

A pilot project lays the groundwork

However, single-cell analysis methods and protocols do not provide a single template that fits all tissues and organs. Each has its own consistency, a different extracellular matrix, or a different cell architecture. The cell populations in the heart are particularly diverse – ranging from the very large heart muscle cells, which make up about 40 percent of the tissue, to connective tissue cells, nerve cells, and immune cells. In a one-year pilot phase, the scientists began by establishing a single-cell sequencing method for the heart, one that now produces reliable results. The Seed Network is now working with valuable human tissue.

Hübner is looking forward to the collaboration, explaining that the Chan Zuckerberg Initiative has succeeded in becoming a truly multinational funding instrument focused on scientific excellence and collaboration. “It enables people all over the world to find others that share common interests and are leaders in their respective fields,” he adds. The Seed Network not only builds on longstanding collaborations like those with the Imperial College London and Stanford University, but also brings in new partners. 

"The concerted work of billions of specialised cells allows the heart to beat 100,000 times every day over a lifetime. Now we have the tools to study how each of these single cells regulates its gene expression and cooperates with its neighbours to keep us alive", says Dr Noseda. She continues, "The study of the heart has evolved from us looking at this marvellous organ like we see Earth from space, to looking at maps, up to now where we can dive into the tissue exploring one cell at a time, and its content. It is like Google maps being able to open the door of each of our homes to explore what is inside".