Heart disease kills 18 million people each year, but the development of new therapies faces a bottleneck: no physiological model of the entire human heart exists -- so far. A new multi-chamber organoid that mirrors the heart's intricate structure enables scientists to advance screening platforms for drug development, toxicology studies, and understanding heart development. The new findings, using heart organoid models developed by Sasha Mendjan's group at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, are presented in the journal Cell on November 28.
Cardiovascular disease is the leading cause of death worldwide, but only a few new therapies are on the horizon. Similarly, one in every 50 babies born suffers from a congenital heart defect -- and again, therapies are few and far between, as we know little why they arise. What is missing in understanding both heart disease and cardiac malformations is a model comprising the major regions of the human heart. Now, the Mendjan team at IMBA presents the first physiological organoid model that includes all the principal developing heart structures and allows researchers to study cardiac disease and development.
In 2021, the Mendjan lab presented the first chamber-like organoid heart model formed from human induced pluripotent stem cells. These self-organizing heart organoids, or Cardioids, recapitulated the development of the heart's left ventricular chamber in the very early days of embryogenesis. "These Cardioids were a proof-of-principle and an important step forward," says Mendjan. "While most adult diseases affect the left ventricle, which pumps oxygenated blood through the body, congenital defects affect mostly other heart regions essential to establish and maintain circulation."
In the new study, the team at IMBA expanded on their previous work. The researchers first derived organoid models of each developing heart structure individually. "Then we asked: If we let all these organoids co-develop together, do we get a heart model that co-ordinately beats like the early human heart?," Mendjan explains.
Unraveling human heart development
After growing left and right ventricular and the atrial organoids together, the researchers were in for a surprise: "Indeed, an electrical signal spread from the atrium to the left and then the right ventricular chambers -- just like in early fetal heart development in animals," Mendjan recalls. "We now observed this fundamental process in a human heart model for the first time, with all its chambers."
While the previous Cardioid model allowed the researchers to study the chamber's shape and tissue organization, the newly developed multi-chamber Cardioids enabled them to go beyond, studying how regional gene expression differences lead to specific chamber contraction patterns and intricate communication between them.
The researchers have already gained insight into early heart development, particularly how the human heart starts beating -- which has not been understood so far. "We saw that as the organoid chambers developed, they performed an intricate dance of lead and follow. At first, the left ventricular chamber leads the budding right ventricular and atrium chambers at its rhythm. Then, as the atrium develops- two days later- the ventricles follow the atrial lead. This mirrors what is seen in animals before the final leaders, the pacemakers, control the heart rhythm," explains Alison Deyett, a PhD student in the Mendjan group and one of the study's first authors.
Source: ScienceDaily
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