Cell Adhesion Shapes Early Embryo Development

At the earliest stage of an embryo’s development, a loosely linked collection of cells must transform into an organised structure. Researchers long believed that simple crowding caused this change: as cells became more tightly packed, the tissue was thought to stiffen and become fixed in position.

New research challenges that view. The force with which neighbouring cells adhere to each other was a much stronger regulator than cell density. Once this grip passed a critical threshold, cells started to form organised tissue before their packing had altered.

A physical developmental signal

For decades, biologists have described early development as the expression of genetic instructions contained within the egg. Nicoletta I. Petridou, a group leader at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, believes that account is incomplete.

Although the egg contains extensive genetic information, those instructions operate in a physical setting, where cells push against one another and bind together.

“The execution of this information is not just molecular,” said Petridou.

Her team examined cell adhesion, the strength of the bond between individual cells. They wanted to know whether adhesion serves only to keep tissue intact, or whether it can also influence the kind of tissue that develops.

Watching a transparent zebrafish embryo

To observe the process directly, the researchers used zebrafish, whose transparent embryos allow cells to be filmed individually. At first, an embryo is simply a rounded cluster of identical, unspecialised cells.

Within several hours, the cluster separates into layers as cells adopt different roles. This marks the beginning of morphogenesis, the process that converts a ball of cells into a body made up of distinct parts. The researchers concentrated on this stage.

Scientists already understood that embryonic tissue can act either like a liquid or like a solid. Previous work had established that these changes are important in constructing a body. One earlier study followed such a transition while a vertebrate embryo extended along its body axis.

Cell packing and cell adhesion

What determines the state of a tissue had remained uncertain. Two likely factors were the density with which cells are packed and the strength of their adhesion. Since both increase and decrease together during development, separating their effects has been difficult.

In earlier research, Petridou’s group showed that the fish embryo passes through a distinct tipping point, moving from a solid-like condition to a fluid-like one and then returning again. They represented the tissue as a network of connected cells and monitored when that network became locked in place.

For the new study, the team made cell-to-cell adhesion an independently controllable factor. Their prediction was that changing adhesion alone could trigger the same transition.

Adhesion as the main control

The researchers identified two methods of altering cell packing without changing the cellular glue. Under one condition, fluid occupying the spaces between cells drained away, forcing the cells closer together.

Embryos grown separately as fragments instead collected excess fluid, which pushed their cells further apart.

Even when compressed, the embryo remained fluid and its cells could still rearrange. The more loosely packed fragment, by contrast, stayed firm. Density had little effect on the outcome; the tissue’s behaviour instead followed the strength of cell adhesion.

To measure each tissue’s resistance to movement, the team used a glass pipette to apply suction and then observed how the tissue flowed.

Until this work, no study had cleanly disentangled packing from adhesion within an embryo. Cell adhesion emerged as the dominant control.

How cell grip organises tissue

The next result was more unexpected. When the team increased adhesion in loosely packed tissue, making it stiffer through cellular grip alone, the cells did not merely stop moving. They began to arrange themselves into an organised layer.

Fluid-filled cavities formed within the tissue. Cells around each cavity then reorganised, directing specialised proteins towards the surface that faced the open space.

That arrangement is a defining feature of epithelial tissue, the sheet-like tissue layers that line the gut.

One reason this could happen was that three cells came together to seal the spaces between them, shutting pores that had previously allowed fluid to pass through. Below a particular adhesion level, those gaps remained open; once the threshold was exceeded, they closed abruptly.

Notably, nothing else was changed. No gene was added and no new chemical instruction was introduced. A stronger bond between cells alone was enough to steer the tissue towards creating structure.

Manipulating cell adhesion

Changing these conditions without disrupting other processes required careful engineering. The researchers developed light-responsive tools that could increase or reduce cellular grip on demand, simply by illuminating the embryo.

In one test, they exposed only one half of an embryo to light. On the illuminated side, a connective protein was broken down and adhesion weakened, while the unlit half continued unaffected.

By combining these light-based tools with precisely controlled changes to the surrounding fluid, the researchers could place tissue in any combination of states: fluid or solid, and loosely or densely packed. This created genetically identical embryos that differed solely in their physical conditions.

What the findings mean for research

The findings provide a clearer picture: a tissue’s physical condition performs an active role in development, and cell adhesion determines that condition. Once adhesion is pushed beyond a threshold, cells start to organise into structured tissue.

Zebrafish embryos are only the first application. Similar phase transitions occur when cancer cells reduce their grip in order to spread, as well as in attempts to grow tissue in the laboratory. Adhesion may offer a new way to influence both processes.

The group is also pursuing a related finding. In a companion study, it showed that the same stiffening process confines the chemical signals that instruct cells what they should become. Physics and chemistry appear to jointly set down the body’s earliest instructions.