They are no bigger than sesame seeds, and they pulse with a hypnotic rhythm. These are human “minihearts,” the first to be created in the lab with clearly beating chambers. The miniature organs, or organoids, mimic the working heart of a 25-day-old human embryo and could help unravel many mysteries—including why babies’ hearts don’t scar after they experience a heart attack.
“This is a great study,” says Zhen Ma, a bioengineer who develops heart organoids at Syracuse University and was not part of the new research. The experiment is “very important” for understanding congenital heart defects and human heart formation—work that has so far relied on animal models, he says.
Although “miniorgans” like brains, guts, and livers have been grown in dishes for more than 10 years, heart organoids have been more challenging. The first ones, comprised of mouse cardiac cells, could contract rhythmically in a dish, but they looked more like a lump of cardiac cells than a proper heart, says Aitor Aguirre, a stem cell biologist at Michigan State University who has created his own beating human heart organoid, described in a preprint posted to Research Square. “An organoid should recapitulate the function of the organ,” he says. With a heart, “You would expect chambers and pumping, because this is what the heart does.”
To create heart organoids whose cells self-organize like those in an embryo, the authors of the new study programmed human pluripotent stem cells, which have the ability to differentiate into any kind of tissue, into various types of cardiac cells. They aimed to create the three tissue layers present in the walls of a heart chamber, one of the first parts of the heart to develop. Next, the researchers immersed the stem cells in different concentrations of growth-promoting nutrients until they found a recipe that coaxed the cells to form tissues in the same order and shape seen in embryos.
After 1 week of development, the organoids are structurally equivalent to the heart of a 25-day-old embryo. At this stage, the heart has only one chamber, which will become the left ventricle of the mature heart. The organoids are about 2 millimeters in diameter and include the main types of cells typically present in this stage of development: cardiomyocytes, epithelial cells, fibroblasts, and epicardium. They also have a clearly defined chamber that beats at 60 to 100 times per minute, the same rate of an embryo’s heart around the same age, the team reports today in Cell.
“When I saw it the first time, I was amazed that these chambers could form on their own,” says lead author Sasha Mendjan, a stem cell biologist at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences. “The amazing thing is that you see immediately whether the experiment worked and the organoid is functional, since it beats—unlike other organs.”
The minihearts, which have so far survived for more than 3 months in the lab, will help scientists see heart development in unprecedented detail. They might also reveal the origins of cardiac problems like congenital heart defects in babies and cardiac cell death after heart attacks, Mendjan says. “You cannot fully understand something until you can re-create it,” he says, loosely quoting the Nobel physicist Richard Feynman.
Mendjan and his colleagues also froze pieces of the organoids to test their response to injury. They saw that cardiac fibroblasts, a type of cell responsible for maintaining tissue structure, migrated to the damaged areas to repair the dead cells, just as in babies that experience heart attacks. It has long been a mystery why babies’ hearts can regenerate after such injury without scarring, unlike those of adults. “Now, we have a controlled and clean system outside of the human body to easily study this process,” Mendjan says.
Aguirre says the next logical step is to connect beating heart organoids to vascular networks and test their ability to pump blood. Mendjan’s team plans to try to adjust the nutrient broth to produce organoids with all four chambers. With such advanced heart organoids, researchers could explore the many developmental heart problems that arise when these additional cavities start to form.
For Ma, growing a more adultlike heart organoid, with all its chambers and structures, is the future of the field. But he doesn’t think this will happen in the next decade. For a complete heartlike organoid, he says, “there is still a long way to go.”
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