"The experiment that led to the discovery was actually an accident. We did not intend to create an organoid," Dr. Sasha Mendjan of the Institute of Molecular Biotechnology in Vienna told Reuters Health by email. "However, the signaling conditions we used were always designed to maximally mimic what we know from the embryo, so in a way this was bound to happen."
"The next steps are creating a model with multiple chambers and getting the heart organoids to further grow in a dish (in a way that) a real heart does," he said.
As reported in Cell, lineage-specific self-organizing organoids had been reported for all major organs except the heart, until Dr. Mendjan and colleagues serendipitously created cardioids - self-organizing cardiac organoids that recapitulate the lineage and architecture of a human heart chamber.
During development, a heart chamber emerges from the mesoderm germ layers. When the team created in vivo-like mesodermal signaling conditions to guide the pluripotent stem cells, the result was self-organization of a heart chamber-like structure that was beating.
The cardioids also replicated the heart's inner endothelial lining, which later contributes to heart vasculature, as well as an outer epicardial layer that directs heart growth and regeneration.
Further investigations showed that upon cryoinjury, cardioids initiated a cell type-dependent accumulation of extracellular matrix - a pathological hallmark of heart disease.
Regarding the potential clinical impact, Dr. Mendjan said, "Most congenital defects are malformations of heart shape in some way. Since this model for the first time develops the shape of a human heart chamber, we can start to understand how these defects come to be in the first place."
"To look into a human embryo at that stage of development is impossible," he noted. "In the lab, we can look at this much more thoroughly with imaging and molecular and genetic methods to really understand what goes wrong in a defect."
The cardioids could also be used to study how the heart responds immediately after a heart attack, he said. "This process that we cannot study in humans now can be studied in detail...in the lab and with high-throughput (methods) to test drugs that affect the process."
Dr. Marcin Iwanicki, Assistant professor in the School of Engineering and Science at Stevens Institute of Technology in Hoboken, New Jersey, commented in an email to Reuters Health, "This is a fantastic report providing evidence that early events associated with heart development, including multicellular organization, can be modeled through careful temporal modulation of morphogenetic signals in tissue culture."
"The quantitative approach to cardioid growth and development warrants improvement of our understanding of signaling pathways that drive human heart development and disease," he said. "These studies provide a significant technological advance in the field of heart development."
"However," he noted, "the technology has to be integrated with in vivo mammalian models of heart defects for future clinical evaluations."
Further, he said, "There was only one male source of iPS cells used in the studies. It would be interesting to include female iPS cells. The female heart is smaller, has thinner walls, and responds to different sets of hormones."
Nonetheless, he added, "This is an important step in the development of robust models of heart development and disease. If personalized iPS technology can be used to derive heart organoids, this could potentially accelerate treatment testing for individuals with heart defects."
SOURCE: https://bit.ly/2S3STM5 Cell, online May 20, 2021
By Marilynn Larkin
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