2023-11-28 18:00:07
heart disease They kill around 18 million people every year in the world., according to the World Health Organization, but the development of new therapies faces a bottleneck: so far there is no physiological model of the complete human heart. Additionally, it is estimated that one in every 50 babies born suffers from a congenital heart defect. Very little is known why they arise and, again, therapies are scarce and ineffective.
Now, the group led by the German researcher Sasha Mendjanat the Institute of Molecular Biotechnology (IMBA), of the Austrian Academy of Sciences, has managed to develop a new multi-chamber cardiac organoid that reflects the intricate structure of the heart.
This work, whose results are presented today in the magazine Cellwill allow advancement in screening platforms for drug development, toxicological studies and understanding of heart development, according to the authors.
In 2021, the Mendjan laboratory presented the first cameral heart mini model formed from human induced pluripotent stem cells. These self-organized cardiac organoids, the cardioidesreproduced the development of the left ventricular chamber of the heart in the first days of embryogenesis.
“These cardioids were a proof of concept and an important step forward,” Mendjan says. “While most adult diseases affect the left ventricle, which pumps oxygenated blood throughout the body, congenital defects They mainly affect other regions of the heart essential for establishing and maintaining circulation.
In the new study, the authors obtained organoid models of each developing cardiac structure separately.
In the new study, IMBA researchers expand on their previous work. First, they obtained organoid models of each developing cardiac structure separately. “Then we asked ourselves: If we let all these organoids develop together, will we get a heart model that beats coordinately like the primitive human heart?” Mendjan says.
Unraveling the development of the human heart
After culturing the left and right ventricular organoids and the atria together, the scientists got a surprise: “Sure enough, an electrical signal propagated from the atrium to the left and right ventricular chambers, just as in early fetal cardiac development in animals.” , recalls the leader of the work, “and we observed for the first time this fundamental process in a model of the human heart, with all its chambers.”
After culturing the left and right ventricular organoids and the atria together, an electrical signal propagated from the atrium to the left and right ventricular chambers, just as in early fetal cardiac development.
While the previous cardioid model allowed them to study chamber shape and tissue organization, the newly developed multichamber cardioids have allowed them to go further, studying how regional differences in gene expression lead to specific patterns of chamber contraction and intricate communication between them.
Researchers have already gained knowledge about the early development of the human heartin particular, about how it starts to beatsomething that was not known until now.
Detection of congenital heart disease and therapy
“We saw that, as they developed, the chambers of the organoid performed an intricate dance of leading and following. At first, the cavity of the left ventricle directs the budding chambers of the right ventricle and atrium in its rhythm. Two days later , when the atrium develops, the ventricles follow the rhythm of the atrium.
Multi-chamber cardioids have allowed us to study how regional differences in gene expression lead to specific patterns of contraction of the cavities and the intricate communication between them.
In addition to studying human development, multi-chamber cardioids allow research specific defects of each cavity. In their proof of concept, Mendjan’s team created a defect screening platform in which they study how teratogens affect [producen alteraciones morfológicas] and mutations known to hundreds of cardiac organoids simultaneously.
It is known that the thalidomidea known teratogen in humans, and retinoid derivatives –used in treatments against leukemia, psoriasis and acne– cause serious heart defects in the fetus. Both substances induced similar and severe defects in specific compartments of cardiac organoids
Similarly, mutations in three cardiac transcription factor genes caused chamber-specific defects observed in human development.
Our tests demonstrate that multi-chamber cardioids reproduce the embryonic development of the heart and can detect disruptive effects throughout this organ with great specificity
Sasha Mendjan, labor leader
“Our tests show that multi-chamber cardioids reproduce the embryonic development of the heart and can detect disruptive effects throughout this organ with great specificity. To do this, we use a holistic approach that analyzes multiple readouts simultaneously,” summarizes Mendjan.
In the future, multichamber cardiac organoids may be used for toxicological studies and to develop new drugs with specific effects on the cardiac chambers.
“For example, the atrial arrhythmias They are widespread, but we currently do not have good drugs to treat them. One of the reasons is that until now there were no models that included all regions of the developing heart working in a coordinated way,” adds Mendjan. And although heart defects are common, including the main cause of spontaneous abortions, they are often unknown. their individual origin.
Atrial arrhythmias are widespread, but we do not have good drugs to treat them. Until now, there were no models that included all regions of the developing heart working in a coordinated manner.
Sasha Mendjan
Cardiac organoids developed from patient-derived stem cells could, in the future, provide insight into the developmental defect and how it can be treated and prevented. Mendjan’s group is especially interested in using multichamber cardiac organoids to better understand heart development: “We now have a basis to investigate the subsequent growth of the heart and its regenerative potential.”
Exclusive license to HeartBeat.bio
The Institute of Molecular Biotechnology has exclusively licensed multi-chamber cardiac organoid technology to HeartBeat.bioa company derived from IMBA, of which Sasha Mendjan is co-founder.
Several HeartBeat.bio researchers have contributed scientifically to the new publication. The company has already translated IMBA’s Left Ventricular Cardioid technology into a 3D drug discovery platform for humans fully automated and integrated that addresses different forms of heart failure.
Licensing the multi-chamber cardioid allows this company to further expand its portfolio of disease models, offering more opportunities to create a cardiac drug discovery pipeline, Mendjan notes.
Reference:
Clara Schmidt, Sasha Mendjan et al. “Multi-chamber cardioids unravel human heart development and cardiac defects”. Cell (2023)
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