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An international team of scientists have developed the first large-scale, single-cell map of the healthy human heart, a major milestone to understanding how the organ performs its vital functions and how cardiovascular diseases manifest in the heart.

The study — published in Nature, a top peer-reviewed publication, Thursday — was co-led by Harvard Medical School professors Christine E. Seidman ’74 and Jonathan G. Seidman ’71, along with collaborators at the Wellcome Sanger Institute, Max Delbrück Center for Molecular Medicine in Germany, and Imperial College London.

Daniel Reichart, a genetics research fellow at the Medical School and co-first author of the study, said the team used single-nuclei RNA sequencing to study around 500,000 individual cells from the healthy hearts of 14 organ donors whose hearts were unsuitable for transplantation due to reasons unrelated to health status.

“We measured the RNA content and were then able to track back what kind of cell type it is, and what kind of function it might have, how they are closely related, and how they are interacting with each other,” Reichart said.

Christine Seidman said this technique was crucial to their study, as traditional methods for examining bulk tissue do not allow researchers to understand the molecular and cellular details of individual cells in the heart.

“Instead of eating pieces of fruit, you have a smoothie where they’re all mixed together,” she said. “Therefore, you can’t really discern whether a signal is coming from one cell type or another.”

“The advent of single-cell sequencing has really revolutionized our understanding of biology because it provides insights into each particular cell that is captured and studied,” she added.

Christine Seidman also noted that research on the heart — using both bulk and single-cell data — lags behind that of other organs due to acquisition difficulties.

“We know actually far less about the heart than we do about lots of other organs,” she said. “It's very unusual to remove a piece of a heart, and cardiac transplantation is also a life-saving therapy but very limited because of the lack of donors.”

By studying individual cells, the scientists discovered subpopulations of known cell types such as cardiomyocytes, which cause the heart to contract and relax, that were not previously known to the cardiology research community, according to Christine Seidman. While researchers have used bulk data to discover differences in cardiomyocytes in the atria and ventricles of the heart, the team’s findings shed light on differences in subtypes even within the ventricles themselves.

“What I didn't know is that if you looked within the left ventricle, you could find five different types of cardiomyocytes, and they’re different based on the RNAs that they express,” Christine Seidman said. “And those five subpopulations, the frequency that they occur in the left ventricle is different than the frequency in the right ventricle.”

She added that studying these subtypes allows researchers to learn about the developmental origins of the cells and how they manifest in an adult, physiologically functioning heart.

“There’s this enormous complexity and intricacy, which really underscores how beautifully constructed the heart is,” Christine Seidman said.

Jonathan Seidman said the study, which features seven female hearts and seven male hearts, could help researchers and medical professionals gain more insight into heart failure, the leading cause of death in the United States.

“It opens up possibilities to answering why men, for example, would have more heart failure than women,” he said. “By understanding the cell atlas, you can’t promise that you’ll understand that better, but it’s certainly a good place to start.”

These efforts are aided by the team’s discovery of the different cardiomyocyte subtypes, which helps pinpoint changes at a much more precise level, according to Christine Seidman.

“We can begin to ask whether they disproportionately affect some of the cardiomyocytes differently than others,” she said. “And that could ultimately help us to understand differences in the expression of diseases, and importantly differences in the way we could treat them by more specifically targeting precise cells.

She added that the group is working to expand their study — which is currently examining 13 hearts from Caucasian donors and one heart from an Asian donor — to a more diverse population, though this is challenging since underrepresented populations are also less frequently organ donors.

“It’s enormously important to be able to understand if there’s, you know, fundamental differences in the architecture of hearts that contribute to heart disease, because if that was true and if we learned how to treat those different populations — their cellular populations — differently, that might make huge differences in people’s health,” Christine Seidman said.

Christine Seidman said the heart cell atlas could also help engineers create artificial hearts for transplantation.

“It’s hard to construct the heart, if you don’t know what’s in it. Now, for the first time, we really have a blueprint of what it takes to make a heart,” she said.

Jonathan Seidman said the map will serve as a “very powerful tool going forward.”

“When you have a human heart cell atlas, you can start to go and explore what are the perturbations, what are the changes that occur in disease, what are the changes that occurred during cardiac development,” he said.

—Staff writer Virginia L. Ma can be reached at virginia.ma@thecrimson.com.