First multi-chamber human heart organoid developed

Cross section of a heart organoid with chambers marked in color

Cross-section of a heart organoid with multiple hollow chambers, with the atrial region in cyan, the left ventricle in white, and the right ventricle in magenta. © Tobias Illmer/IMBA

Researchers have been trying to grow organs and their precursors, organoids, in the laboratory for a long time. Now, for the first time, a team has succeeded in generating such a human heart organoid with multiple cardiac chambers. The mini organ reflects the complicated structures of our heart better than previous models. The scientists report that it is now possible to research more precisely than before how our heart develops and which defects underlie heart disease. This also makes it easier to develop new medications for heart disease.

Diseases of the cardiovascular system are the most common cause of death worldwide and around one in 50 newborns suffer from a congenital heart defect. However, because so far little is known about the molecular causes of the defects, there are only a few treatment options. Research is stalling because there is no model that covers the entire human heart. However, this is important because the diseases affect different areas of the heart. “While most diseases in adults affect the left ventricle, which pumps oxygen-rich blood throughout the body, congenital defects primarily affect other regions of the heart that are essential for establishing and maintaining blood flow,” explains Sasha Mendjan from the Institute of Molecular Biotechnology Austrian Academy of Sciences (IMBA).

New cardioids combine different areas of the heart

A research team led by his IMBA colleague Clara Schmidt has now developed several three-dimensional cell models, so-called organoids, which include the most important structures of the human heart: the atrial region, the two heart chambers and the structures for their blood inflow and outflow. In preliminary work, the team had already produced a chamber-like heart organoid, a so-called cardioid, from human stem cells. This resembled the left ventricle of the heart at a very early embryonic stage. In their new study, the researchers have now also developed corresponding organoids from early stages of development of the right ventricle, the atria and the entrance and exit areas of the two ventricles - initially separately from each other.

Schmidt and her colleagues then tried to use the individual parts to form a simplified heart organoid with multiple chambers that beat in a coordinated manner like the early human heart. To do this, they had the individual organoids for the left and right ventricles and an atrium developed together and grew together. With success: “In fact, an electrical signal spread from the atrium to the left and then to the right ventricular chamber – just like in early fetal heart development in animals,” says Mendjan. “We have now observed this fundamental process for the first time in a human heart model with all its chambers,” he adds.

With the new three-chamber cardioid model, researchers can now examine the organization of the heart tissue within individual areas in more detail and also understand more precisely why the chambers alternately contract in their typical rhythm. Schmidt and her colleagues have already found new clues about how our heart finds its rhythm. Accordingly, the left ventricle initially sets the rhythm of the developing right ventricle and atrial ventricle. Two days later, the two chambers followed the lead of the forecourt. “This reflects what you see in animals before the later leaders, the specialized pacemaker cells, control the heart rhythm,” explains co-author Alison Deyett from IMBA.

Search for causes of heart defects and new medications

The model also has therapeutic benefits: In the future, the new organoids can be used to investigate much more quickly what causes heart malformations in the embryo. To this end, Schmidt's team has already developed a screening platform that can be used to analyze hundreds of organoids at the same time. First, the scientists applied gene mutations and chemicals known to promote deformities in fetuses and demonstrated that these also occurred in their organoids. In the future, the technology can now be used to test the effects of many other substances, genetic changes and environmental influences.

“Our tests show that multi-chambered cardioids can mimic embryonic heart development and reveal disruptive effects on the entire heart with high specificity,” reports Mendjan. The aim is to find the individual cause of heart defects. In addition, the new organoids can be used to localize these defects in the heart and thereby develop new drugs against common heart diseases. Unlike previous preparations, they are intended to have a specific effect on the affected areas of the heart, for example the atria. “Atrial arrhythmias are widespread, but we currently don’t have any good medications to treat them,” explains Mendjan. The scientists report that personalized heart organoids made from patient stem cells could also be used in the future.

The researchers have patented the technology of heart organoids with multiple chambers and, with their spin-off company AG, have already generated a fully automated research platform to find new drugs to treat various forms of heart failure in humans. Overall, the newly developed model represents an early and simplified developmental stage of our heart. For example, it does not take into account how heart valves and coronary vessels form, and in general how the heart grows and matures. The organoids therefore cannot reveal heart defects that occur at a later point in time, the researchers report.

Source: Clara Schmidt (IMBA) et al., Cell, doi: 10.1016/j.cell.2023.10.030

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