A first cell atlas of our heart

Heart muscle cells

Human heart muscle cells grown from stem cells (Image: Sebastian Diecke / MDC)

Our heart is a complex organ – the engine of our life. But only now does the first cell atlas of the heart reveal the diversity of cellular components this organ has. To map them, researchers analyzed the gene activity and function of half a million cells from six different regions of the heart. They discovered numerous previously unknown subtypes of heart cells, but also an unexpected difference between the sexes: women have more heart muscle cells in their heart chambers than men.

Usually we are barely aware of the regular beating of our heart. Our pumping organ performs tremendously in the process: it contracts more than 100,000 times a day and pumps oxygen-rich blood through our veins, adapting its speed flexibly to our movements or stressful situations. The heartbeat is the result of a complex interaction between actors: As in an orchestra, thousands of cells have to coordinate their activities with one another. But how this happens in detail and which cells in the heart work and how has only been partially clarified. Most heart cells can only be cultivated and examined in the laboratory to a limited extent and their interaction can only be researched on an intact organ. However, the hearts of laboratory animals such as mice differ in many respects from the human pumping organ.

14 human hearts and 500,000 cells analyzed

To gain more insight into the cellular structure of the heart, an international research team led by Sarah Teichmann from the British Wellcome Sanger Institute and Norbert Hübner from the Max Delbrück Center for Molecular Medicine in Berlin started the “Human Heart Cell Atlas” project three years ago . The objects to be examined were 14 hearts – seven from men and seven from women – which were originally intended for organ donation. Because these hearts were out of the question for a transplant, these organs were available for the project – a rare stroke of luck. The researchers took cell samples from six areas of the heart and first determined the individual genetic characteristics of these cells using high-throughput sequencing. “This means that for the first time we have a kind of zip code that tells us which population each cell belongs to,” explains co-author Christine Seidman from Harvard University.

In the next step, the scientists analyzed the transcriptome of the various heart cell types – the portion of the genetic code read from the genetic material and present in the form of RNA. It reveals which genes are currently active in the cells and which proteins are currently being produced. The result of this work is a heart atlas showing the cell type, position and activity of almost half a million different heart cells. “I can only sum up this achievement in one word: monumental,” comments cardiologist Douglas Mann from Washington University in St. Louis, who was not involved in the study. “This is a really great achievement and it will be an extremely important reference source for research in this area.”

Unexpected differences between men and women

Specifically, the analyzes revealed an unexpected cellular diversity in our pumping organ. In each of the six heart areas, specific combinations of different cell types were found, from supporting cells to muscle cells and immune cells to the vascular cells of the supplying veins. All previously known cell types of the heart also have numerous, partly previously unknown subtypes. There is not just one heart muscle cell, but many different cardiomyocytes, some of which have completely different functions. The gene expression patterns suggest that some of them can handle a much higher metabolic rate than others. The scientists cannot yet say why this is so. There were also different patterns of activity in the fibroblasts, the connective tissue cells of the heart. “Some produce the extracellular matrix using different processes, others rebuild the scaffolding, and still others communicate with immune cells in their immediate vicinity,” reports Huebner’s colleague Henrike Maatz.

What was also unexpected was the observation that women have more muscle cells and fewer connective tissue cells in their heart chambers than men – although female hearts are generally smaller than male ones. This could possibly explain why women are less likely than men to develop cardiovascular diseases. “That is fascinating, but the result is based on only seven hearts of each gender,” emphasizes Maatz. “We have to see whether this result can withstand further investigations.” According to the scientists, their heart atlas now offers many new points of contact for research into heart diseases. “The atlas will lead to a new understanding of heart health and disease, new treatments and possibly even new ways to regenerate damaged heart tissue,” says Teichmann. Because in order to understand what goes wrong with the various forms of heart disease, one must first know how the healthy heart works at the cellular level – and the cardiac atlas now contributes to this.

Source: Nature, doi: 10.1038 / s41586-020-2797-4

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