About 18 million people die each year from cardiovascular diseases, making it the number one killer globally. Moreover, heart defects are the most prevalent birth defects in children. Currently, a major bottleneck in developing regenerative therapies and in understanding human heart malformations are missing human physiological models of the heart.
Now, the research group of Sasha Mendjan at IMBA established human self-organizing cardioids that recapitulate the lineage architecture of the heart. Dr. Mendjan explains: “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”.
During development, a heart chamber emerges from the mesoderm germ layer. The researchers thus established in vivo-like mesodermal signaling conditions guiding pluripotent stem cells. “Amazingly, this led to self-organization 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 it does not require addition of exogenous extracellular matrix like many other organoid models,” explains Dr. Mendjan.
Besides a beating myocardial layer, a functional heart also contains an inner endothelial lining that later contributes to heart vasculature, and an outer epicardial layer that directs heart growth and regeneration. Cardioids recapitulate this three layered structure, shaping a heart chamber-like structure.
Richard Feynman once wrote: “What I cannot create, I do not understand “; this principle guides the Mendjan lab to recreate and understand human heart development and defects. It allowed the scientist to tease apart how signaling and transcription factors control the size of a cardioid chamber and separate cardiac layers. For instance, the dramatic chamber cavity loss observed in children with Hypoplastic Left Heart Syndrome, phenocopied in cardioids by the disruption of a transcription factor linked to this defect.
The self-organizing organoid field has revolutionized biomedical research over the past decade, and the heart was the last major inner organ missing such a model. “Cardioids bear incredible potential to unravel developmental mechanisms and human congenital heart defects. As the system is physiological and scalable, this opens up huge possibilities for drug discovery and regenerative medicine,” says Sasha Mendjan.
Link to the publication on bioRxiv
IMBA - Institute of Molecular Biotechnology - is one of the leading biomedical research institutes in Europe focusing on cutting-edge stem cell technologies, functional genomics, and RNA biology. IMBA is located at the Vienna BioCenter, the vibrant cluster of universities, research institutes and biotech companies in Austria. IMBA is a subsidiary of the Austrian Academy of Sciences, the leading national sponsor of non-university academic research. The stem cell and organoid research at IMBA is being funded by the Austrian Federal Ministry of Science and the City of Vienna.