Scientists identify mechanisms of early heart development in Zebrafish

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A female specimen of a zebrafish (Danio rerio) breed with fantails
A female specimen of a zebrafish (Danio rerio) breed with fantails

Cardiovascular disease is one of the leading causes of death in the world with approximately 30% of global mortality attributed to it. Cardiovascular disease conditions lead to damage of cardiac muscle cells resulting in defective heart function.

Stem cell therapy, though a relatively young science, is one of the upcoming treatment options for such diseases in the near future. In principle, stem cells from embryos can be made to differentiate into many functional cell types including heart cells, which can be effectively used to replace damaged cells in heart patients. To achieve this, scientists are constantly trying to understand the developmental process by which the heart is formed from various progenitors in a growing embryo. Once we understand this pathway at an organismal level, efforts can be made to use these stem cells for regenerative medicine.

A team of scientists led by Bruno Reversade from Singapore and Ian Scott from the University of Toronto have come together to study heart development in the Zebrafish model.

Studies of heart development in zebrafish embryos could lead to new stem cell therapies. Image credit: Philipp Keller, Bill Lemon, Yinan Wan and Kristin Branson, Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Va.
Studies of heart development in zebrafish embryos could lead to new stem cell therapies.
Image credit: Philipp Keller, Bill Lemon, Yinan Wan and Kristin Branson, Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Va

Zebrafish, scientifically called Danio rerio, is one of the powerful models for studying various organ functions. Although there are major structural differences between zebrafish and humans, there are strong similarities at the genetic and morphological levels. One of the biggest advantages of using zebrafish is that unlike mice, rats or monkeys, zebrafish embryos are transparent and hence provide a tractable system for visualizing these important developmental processes in situ .

Heart development in Zebrafish

During embryonic development, early heart development requires the activation of one of the important signaling pathways called Nodal or TGFβ pathway. Depending on the activation levels of Nodal, different cells become different stem cell types. Hence, there has to be a mechanism for fine-tuning of this signaling to produce these activity thresholds. Scientists from these two groups have recently identified the candidates involved in this fine-tuning.

The Apelin receptor- a distant rheostat

Researchers recently identified a mutation, which leads to zebrafish with no heart at all. This suggests that this mutation somehow alters an early developmental process in heart formation. Interestingly, this gene encodes for a protein called Apelin receptor. So how does the Apelin receptor affect heart development? Scientists revealed that mutation in this receptor caused lower levels of Nodal signaling in mutant embryos as compared to the normal ones, thus failing to induce the formation of cardiac stem cells. When Nodal activity is artificially elevated in embryos that lack the Apelin receptor, they were able to develop hearts further confirming the role of Apelin receptor in this pathway.

A detailed understanding of this molecular cross-talk could help in the derivation of specific cell types from human embryonic stem cells for regenerative medicine, says Bruno Reversade, a human geneticist at the A*STAR Institute of Medical Biology, who co-led the investigation.

Further, this collaborative study showed that the Apelin receptor does not work in cells that produce or receive Nodal signals, suggesting that the Apelin receptor modulates Nodal signaling levels by acting in cells that lie between the cells that release Nodal signals and the cardiac progenitors.

In brief, this receptor functions as a distant regulator for fine-tuning the expression of the Nodal pathway during early stages of heart development ensuring proper cardiac development. One important area of future study is to determine whether modulating the levels of this receptor can prove useful for patients with various heart disorders.

Original article can be found here: https://elifesciences.org/content/5/e13758