During embryonic development, a single fertilized egg cell forms an entire organism with many different cell types. How do a seemingly chaotic pile of dividing cells become well-defined tissues? Researchers have now identified factors that influence the adhesion between cells and thus ensure that cells of the same type cluster together more than cells of different types.
A few hours after fertilization, an egg begins to divide. Different cell types differentiate over time. They begin to form spatial patterns that later become different tissues and structures in the organism. How exactly this process, known as morphogenesis, works has been a topic of concern to researchers for decades and is still a mystery. Researchers led by Sean Megason from Harvard Medical School have now discovered an important control mechanism in zebrafish embryos that enables cells to organize themselves.
The same cell types prefer to stay together
To do this, the researchers investigated how strongly different cell types in the spinal cord of the zebrafish embryos adhere to one another. The adhesion between the cells, the so-called adhesion, is relevant because cells lying next to one another are often torn apart during embryonic development when cells rearrange and new cells are formed. The researchers simulated this in the laboratory by pulling two or three cells apart with micropipettes and measuring the force required. In all three cell types examined, it was found that the adhesion between cells of the same type was strongest.
In addition, the researchers analyzed which molecules are responsible for the various adhesive properties. In doing so, they discovered that each cell type has a specific adhesion profile in which the adhesion molecules involved are developed to different degrees. This adhesion code determines which of its neighbors a cell prefers to stay in contact with. “All three adhesion molecules that we looked at are produced in different amounts in each cell type,” says first author Tony Tsai. “Cells use this code to preferentially attach to cells of their own type, which allows different cell types to separate during patterning. But cells also hold some degree of adhesion with other cell types as they have to work together to form tissue. By putting these local rules of interaction together, we can shed light on the global picture. “
More than just morphogens
But how do these different adhesion codes come about? What causes the cells to produce the corresponding molecules in different quantities? According to the researchers’ results, higher-level signaling molecules, so-called morphogens, are responsible for this. These regulate cell fate and pattern formation during embryonic development. There are various theoretical models for the precise functioning of these morphogens. One of the most important is the French flag model. According to this model, morphogens are released from individual sources in the embryo, with nearby cells being exposed to higher amounts of the signaling molecule than more distant cells. The amount of the signaling molecule determines which cellular program is activated. Concentration gradients of morphogens therefore “paint” patterns on groups of cells, which is reminiscent of the different colored bands of the French flag.
However, this model has limitations. In previous studies, Megason and colleagues have shown that morphogen signals can be inaccurate, especially at the borders of the “flag”. In addition, cells in a developing embryo are constantly dividing and moving, which can disrupt the morphogen signal. Nevertheless, the cells sort themselves into precise patterns. According to the scientists, this could not be explained with the French flag model alone.
Combination of two theoretical models
The new findings on the specific adhesion between cells provide a supplementary explanation and support another theoretical model: the hypothesis of differential adhesion. This model assumes that certain cells, depending on their type, adhere to one another more strongly than others. Megason’s team could confirm that. The results suggest that the interplay of morphogens and adhesive properties enables cells to organize themselves so precisely. Megason explains: “The French flag model gives a rough sketch and the differential adhesion then provides the exact pattern. The combination of these strategies seems to be the key to how cells form spatial patterns as the embryo forms. “
The researchers now want to investigate further cell types in order to gain more detailed insights into the underlying processes. In the long term, their findings could help to manufacture artificial tissues and organs, for example for transplants or for drug tests. “The production of artificial tissues for research or medical applications is a crucial goal, but so far we still don’t know enough about the basics,” says Tsai. “If we understand how the cells in an embryo are able to manufacture the components of an organism so safely and reproducibly, we can learn a lot from them.”
Source: Tony Tsai (Harvard Medical School) et al., Science, doi: 10.1126 / science.aba6637