According to the World Health Organization, around 18 million people worldwide die from heart disease every year, but the development of new therapies faces a bottleneck: To date, there is no physiological model of the entire human heart. In addition, it is estimated that one in 50 babies born suffers from a congenital heart defect. Very little is known about why they arise, and here too there are few and ineffective treatments.
The group is now led by the German researcher Sasha MendjanThe Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences has succeeded in developing a new multi-chamber heart organoid reflects the complicated structure of the heart.
This work, the results of which are presented in the magazine today cellwill enable advances in screening platforms for drug development, toxicology studies and understanding of heart development, according to the authors.
In 2021, the Mendjan laboratory presented the first mini model of a heart formed from chambers human-induced pluripotent stem cells. These self-organizing cardiac organoids, or kidneyreproduced the development of the left ventricle in the first days of embryogenesis.
“This cardioid pattern was a proof of concept and an important step forward,” says Mendjan. “While most diseases in adults affect the left ventricle, which pumps oxygen-rich blood throughout the body, Congenital defects They primarily affect other regions of the heart that are important for building and maintaining blood circulation.
In the new study, IMBA researchers expand on their previous work. First, they separately obtained organoid models of each developing heart structure. “Then we asked ourselves: If we develop all these organoids together, will we get a heart model that beats in a coordinated manner like the primitive human heart?” says Mendjan.
Elucidate the development of the human heart
After co-culturing the left and right ventricular organoids and atria, the scientists experienced a surprise: “In fact, an electrical signal propagated from the atrium to the left and right ventricular chambers, just as in early fetal heart development in animals,” recalled says the leader of the work, “and we observed this fundamental process for the first time on a model of the human heart with all its chambers.”
While the previous kidney model allowed them to study chamber shape and tissue organization, the newly developed multi-chamber kidney models allowed them to go even further and examine how regional differences in gene expression lead to specific patterns of chamber contraction and intricate communication between them.
Researchers have already gained knowledge about this early development of the human heartespecially about how it starts to beatsomething that was previously unknown.
Detection of congenital heart defects and therapy
“We saw that the organoid’s chambers performed a complicated dance of leading and following as they developed. First, the cavity of the left ventricle directs the rhythm of the developing chambers of the right ventricle and the atrium. Two days later As the atrium develops, the ventricles follow the rhythm of the atrium.
In addition to studying human development, multi-chambered kidneys also enable research specific defects of each cavity. In their proof of concept, Mendjan’s team created a Error screening platform They study how known teratogens (causing morphological changes) and mutations simultaneously affect hundreds of cardiac organoids.
It is known that the Thalidomidea known teratogen in humans, and Retinoid derivatives – used to treat leukemia, psoriasis and acne – cause serious heart defects in the fetus. Both substances caused 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 show that multichambered kidneys can replicate the embryonic development of the heart and detect disruptive effects throughout the organ with high specificity
“Our tests show that multi-chamber kidneys replicate the embryonic development of the heart and can very specifically detect disruptive effects throughout this entire organ. To do this, we use a holistic approach that analyzes several readouts at the same time,” summarizes Mendjan.
In the future, multichamber cardiac organoids could be used for toxicological studies and development new drugs with specific effects on the heart chambers.
“For example the Atrial arrhythmias They are common, but we currently have no good medications to treat them. “One of the reasons for this is that until now there have been no models that coordinately include all regions of the developing heart,” adds Mendjan. And although heart defects are common and are the leading cause of spontaneous abortion, they are often unknown. their individual origins.
Atrial arrhythmias are common, but we don’t have good medications to treat them. To date, there have been no models that coordinately include all regions of the developing heart.
This led to the development of cardiac organoids patient-derived stem cells could provide insight into how the development error can be treated and prevented in the future. Mendjan’s group is particularly interested in using multi-chambered heart organoids to better understand heart development: “We now have a basis for studying the subsequent growth of the heart and its regenerative potential.”
Exclusive license for HeartBeat.bio
The Institute of Molecular Biotechnology has exclusively licensed the multi-chamber heart organoid technology to HeartBeat.bio, a spin-off company of IMBA Sasha Mendjan is co-founder.
Several HeartBeat.bio researchers contributed scientifically to the new publication. The company has already implemented IMBA’s left ventricular cardioid technology into a 3D human drug discovery platform fully automated and integrated that treats various forms of heart failure.
Licensing the multi-chamber cardioid pattern allows this company to further expand its portfolio of disease models, providing more opportunities to build a cardiac drug discovery pipeline, Mendjan notes.
reference:
Clara Schmidt, Sasha Mendjan et al. “Multi-chambered kidneys unravel human heart development and heart defects.” cell (2023)