The heart is the first functional organ in the body. Unfortunately, not always does the heart function as it should: approximately one percent of all children as born with a congenital heart defect. The causes for such defects, which include issues with heart valves or the chamber septum, remain only vaguely understood. Recent research is slowly fulling these gaps: for instance, work by the molecular biologist Christian Mosimann and his team can now visualize the formation of the heart in zebrafish from the first cell to the formation of heart chambers. This work provides a further step towards a deeper understanding of how congenital heart defects arise.
The chambers of the heart form the engine driving the exchange and the distribution of oxygen throughout life. Congenital defects in the left heart chamber, the so-called left ventricle that is in charge of pumping blood throughout the body, require surgical repair or even transplantation of a healthy heart in the affected child. Nonetheless, it remains unclear how many congenital heart defects arise. Basic research using the mouse and the zebrafish models critically increased our knowledge of the earliest events of heart development.
Now, the team of Christian Mosimann, Assistant Professor at University of Zürich, could document for the first time the entire process of how the left ventricle equivalent develops from initial heart-forming cells. The multi-year research effort arose in close collaboration with the laboratory of Dr. Daniela Panakova at the Max-Delbrück Center in Berlin, Germany.
Watching the early heart form
Zebrafish develop their heart in a literal heartbeat: within 24 hours of development, the optically transparent zebrafish embryo has already formed a beating heart with all main features and has set up blood flow. Prof. Mosimann and his team apply latest transgenic technologies for the live imaging of the developing processes within the living embryo. The graduate students Anastasia Felker and Karin Prummel had developed transgenic zebrafish strains that label the cells involved in heart formation with fluorescently glowing proteins. Although previous studies had used similar approaches, the team’s work achieved their breakthrough of labeling the entire heart-forming procedure with previously undiscovered genetic material that becomes active in early heart development.
The resulting microscopy movies and data now revealed for the first time that the zebrafish ventricle forms from a continuous flow of cells, which communicate with each other to coordinate their interactions and identity within the heart. In a second publication in the same edition of Nature Communications, the team of Dr. Panakova further documented how the heart chambers expand and balloon to generate a functional heart. The required mechanism to control the required cell arrangements and communication was uncovered with support of genetically edited zebrafish strains generated in the Mosimann lab.
From fish tank to bedside?
The new results clarify previous work in the field and connect directly to findings in mice, underlining the conservation of fundamental processes involved in heart development. “These similarities suggest an ancient developmental principle at the base of heart development, which we expect to be also valid in humans”, adds Prof. Mosimann. The possibility to observe heart chamber formation live in the zebrafish embryo enables now further research to find causal connections between genetic mutations and congenital heart defects in children. With their new basic research findings, the scientists hope to contribute to improving diagnostics and genetic counselling for congenital heart defects in the clinic.
Continuous addition of progenitors forms the cardiac ventricle in zebrafish.
Felker A, Prummel KD, Merks AM, Mickoleit M, Brombacher EC, Huisken J, Panáková D, Mosimann C.
Nat Commun. 2018 May 21;9(1):2001. doi: 10.1038/s41467-018-04402-6.
Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity.
Merks AM, Swinarski M, Meyer AM, Müller NV, Özcan I, Donat S, Burger A, Gilbert S, Mosimann C, Abdelilah-Seyfried S, Panáková D.
Nat Commun. 2018 Jun 4;9(1):2161. doi: 10.1038/s41467-018-04566-1.
University of Zurich
Prof. Dr. Christian Mosimann
Institute for Molecular Life Sciences