Cardiovascular diseases are estimated to kill around 18 million people annually, earning them a top seat among the leading causes of death globally. Studying the diseases of this vital organ has been a tricky task as finding a suitable model (we can’t very well go tinkering with volunteers’ life pumps) for research. Now, a new study published in the journal Cell appears to have found one possible solution: a self-organizing heart organoid that can beat after eight days of development.
Organoids are artificially grown cell masses created to resemble the physiological structure and function of the real thing. They have been used in research for pretty much every major organ in the body except for the human heart – that was, until scientists at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) created cardioids.
"Cardioids are a major milestone,” said co-author Dr Sasha Mendjan of the IMBA in a statement. “Our guiding principle is that for an in vitro tissue to be fully physiological, it also needs to undergo organogenesis. We were able to achieve this, using the developmental principles of self-organization - which makes it such an exciting discovery".
Organogenesis is a process seen in embryonic development whereby cells specialize to create functional organs. Using human pluripotent stem cells, the team was able to create cardioids capable of organizing themselves in this way, developing into chamber-like structures containing a cavity, much like the atrium and ventricles of the human heart.
By creating conditions that mimic that of early embryonic development, the researchers were able to guide the pluripotent stem cells towards forming cardioids. Not only did this give rise to chamber-like structures that began beating halfway through day seven of development, but it also established an inner layer that mimicked the three-layered endothelial lining seen in the human heart.
“For the first time, we could observe something like this in a dish,” continued Mendjan. “It is a simple, robust and scalable model, and does not require addition of exogenous extracellular matrix like many other organoid models."
By establishing the signaling and transcription factors that dictate the construction of the cardioids’ chambers, the team was able to manipulate these to create organoids that mirrored human disease. One example included Hypoplastic Left Heart Syndrome, a condition that leads to the left side of the heart not forming correctly. By disrupting the transcription factor associated with this condition, the team was able to create cardioids that carried the same issues, meaning the disease could be observed ex-vivo.
This kind of petri-dish-side-seat observation even yielded new insights into the effects of myocardial infarction (heart attacks) by mimicking the onset of disease using cryoinjury (injury by freezing) on the cardioids. Affected organoids were found to accumulate extracellular matrix proteins, which are said to be an early hallmark of heart disease.
Cardioids are something of a final puzzle piece for biomedical research that leans on model organoids to study major organs, and will likely open many doors for the future research of human heart disease. "Cardioids bear incredible potential to unravel human congenital heart defects,” said Mendjan. “As the system is physiological and scalable, this opens up huge possibilities for drug discovery and regenerative medicine.”