Researchers from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) have developed self-organising heart organoids, known as cardioids, that recapitulates a heart chamber-like structure.
The heart is fickle, and in more ways than one. Of the various ailments plaguing the human body, heart diseases are among the most complex to resolve. Claiming about 18 million lives each year, cardiovascular disease, a blanket term for complications affecting the heart and blood vessels, is one of the primary causes of death globally.
Over the past decades, biomedical researchers have innovated on organoid models to replicate organ functions and simulate disease pathogenesis. Human physiological heart models, however, have posed a great challenge in development due to the complex nature of the heart and blood network. This shortage of effective models to imitate developmental and injury response processes have stood in the way of our understanding of heart defects and developing regenerative therapies.
In this ground-breaking work published in Cell, a research group from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has successfully crafted self-organising heart organoids that are capable of mimicking the three-layered structure of a heart chamber. These cardioids show great potential as a model to study cardiovascular disorders and heart malformations.
"Cardioids are a major milestone. 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,” explained Sasha Mendjan, a member of the research team.
During normal development, heart chambers are formed as a result of cells differentiating from the mesoderm germ layer. To replicate this process and construct the organoid, the researchers simulated in vivo-like mesodermal signalling conditions thereby stimulating pluripotent stem cells to differentiate into specialised chamber-like structures. Apart from a beating heart chamber, the cardioid also contained an inner endothelial lining that would grow into the heart vasculature and an outer epicardial layer that regulates heart growth and regeneration.
"Amazingly, this led to self-organisation of a heart chamber-like structure that was beating. For the first time, we could observe something like this in a dish. It is a simple, robust and scalable model, and does not require addition of exogenous extracellular matrix-like many other organoid models," said Mendjan.
Furthermore, the researchers went on to investigate how signalling and transcription factors stimulate cardioid formation. By disrupting a specific transcription factor, they were able to replicate the marked chamber cavity loss observed in patients with Hypoplastic Left Heart Syndrome. They were also able to assess the impact of myocardial infarction (or heart attack) by subjecting the cardioid to injury by freezing, a method that inflicts damage similar to myocardial infarctions. From this experiment, they observed for the first time in a dish that this injury prompted the accumulation of extracellular matrix proteins, an indicator of both regeneration and fibrotic heart disease.
As the last major inner organ missing such a physiological model, the heart can now be more thoroughly studied through cardioids, thereby providing us with a better understanding of human congenital heart defects. In future, this system may be scaled to bring more possibilities for drug discovery and regenerative medicine.
Source: Hofbauer et al. (2021). Cardioids reveal self-organizing principles of human cardiogenesis. Cell.