Morphologies are molecules that travel from biological cell to cell to model tissues in the embryo. These molecules are not only important for embryo during development, but also for adults during tissue repair. However, how these morphologies are distributed to ensure patterning occurs is still not fully understood.
Schematic image of Wnt signal in cardiac tissue. nt ligand is secreted from the epidermis (left cell). Wnt signaling is activated in a concentration-dependent manner (rounded arrows), induces Fzd7 expression and limits Wnt ligand propagation. Distribution of sFRP1 protein is restricted by N-acetyl HS, which is abundant in the outer region of the cardiac dermis. Image credit: Yamamoto et al., ELife 2022, CC BY-NC
Using a combination of experiments and mathematical modeling, a research team from the University of Tokyo and their international collaborators learned more about the role morphologies play in tissue modeling. The results are relevant to medical applications, such as drug design. The team’s findings are published in the journal eLife.
Wnt morphology has emerged as a key regulator of cardiac development in vertebrates. These Wnt proteins are molecules that play an important role in cell growth. However, scientists are still unclear exactly how Wnt regulates heart development. There are differences between classes of vertebrates and redundancy in some species.
However, scientists can study how Wnt regulates heart growth in Xenopus, an aquatic frog native to sub-Saharan Africa. The Xenopuswith a three-chamber lung and heart, cost-effective and useful for scientists studying human diseases.
In Xenopus During the development of the heart, the scientists determined that the epidermis sends out the Wnt6 form, the outer layers of cells that make up the skin, to shape the cardiac mesoderm, the group of cells in the embryo that will form the heart. From this model, a relatively thin pericardium (the membrane surrounding the heart) and a wide myocardium (the muscle tissue of the heart) develop.
Scientists are still working to better understand how Wnt6 morphogen distribution is regulated to ensure the regenerative site of the pericardium and myocardium in the cardiac mesoderm. “It remains unclear how a reproducible model can be achieved with diffusing molecules, especially when that model involves differentiation of thin tissues.” Takayoshi Yamamoto, an assistant professor at the University of Tokyo and the first and corresponding author on the paper.
Scientists know that during early embryonic development, the range of Wnt8 morphological signaling is precisely regulated by heparan sulfate and the secretion of Wnt-binding proteins, including Frzb (also known as sFRP3). Heparan sulfate is a carbohydrate that is important for embryonic development. Wnt signaling is one of the key processes that pattern formation during embryonic development. The team wondered whether mechanisms similar to those operating in early embryos regulate the distribution of Wnt6 morphogen in the cardiac mesoderm.
The Wnt receptor, Frizzled7, is essential for heart development. Expression of Frizzled7 is increased by Wnt signaling in neurogenesis in Xenopus and in the development of human embryonic carcinoma cells, but no such reports in cardiac development. So, the team focused their research to analyze how Wnt signaling occurs in heart development, focusing on the extracellular components – the cell surface receptor Frizzled7, sFRP1 (an inhibitor of the cell surface). Wnt6 inhibitors can also pass from cell to cell) and heparan sulfate.
“With a combination of experiments and mathematical modeling, this receptor feedback appears to be essential for shaping a large gradient of Wnt signaling. In addition, computer simulations reveal that this feedback confers robustness against variants of Wnt ligand production and allows the system to reach steady state rapidly,” said Yamamoto. .
The Wnt6 and sFRP1 molecules not only regulate the normal development of the heart in the embryo, but also regulate repair and regeneration after myocardial injury, such as in the case of myocardial infarction or heart attack. .
“Our findings will have implications for medical applications, such as drug design, as cell surface molecules such as Frizzled or a specific modification of heparan sulfate or even a molecule that is secretes sFRP1, which often provides better drug targets than molecules inside cells. In order to reveal the exact regulation of morphological substances and to consider medical applications, the regulatory mechanisms of these components must be further investigated, said Yamamoto.
Source: University of Tokyo
