Squame Formation and Skin Disease

Skin is our body’s most ardent defender against pathogens and other external threats. Its outermost layer is maintained through a remarkable transformation in which skin cells swiftly convert into squames—flat, dead cells that provide a tight seal between the living portion of the skin and the world outside.

“Throughout our lifetime, squames are continually being shed from the skin surface and replaced by inner cells moving outward,” says Elaine Fuchs of Rockefeller University. “We’ve identified the mechanism that allows skin cells to sense new changes in their environment and very quickly deploy instructions to drive squame formation.”

Published today in Science, the research also provides insight into how errors in this mechanism might lead to skin conditions like atopic dermatitis and psoriasis.

Just before they turn into squames, skin cells contain darkly stained protein deposits that resemble the droplets you see when oil and vinegar and mixed together. This phenomenon, called phase separation, occurs when liquids with mismatched properties come together: The oil prefers to be in the company of other oil, so it separates from the water-based vinegar.

Phase separation is also thought to take place inside cells, where the equivalent of oil droplets are poorly understood structures that are not bound by lipid membranes. The team suspected that in skin cells, the dark protein deposits—known as keratohyalin granules—form through phase separation and carry molecular messages that prompt the cells to flatten and die upon release.

The researchers developed a technique to visualize phase separation dynamics without disrupting a cell’s normal processes. They created mice with a phase separation sensor—a biomolecule that emits green light under the microscope when keratohyalin granules form and then dissipates when the granules disassemble.

Using this method, the researchers showed that a protein called filaggrin (which is mutated in some skin conditions) plays a key role in granule formation. When they engineered filaggrin proteins to mimic mutations associated with atopic dermatitis, skin cells could no longer form normal granules. “We suspect that this lack of phase separation contributes to defects in building the skin barrier, resulting in the inflamed, cracked skin that is seen in these conditions,” Quiroz says.

Senior author Elaine Fuchs adds that the work opens new avenues for developing treatments for filaggrin-linked skin diseases. “Most treatments developed thus far have been focused on suppressing the immune system, but our findings suggest that we should be looking more closely into the barrier itself,” she says.

Image: The formation of droplets (green) drives a rapid transformation of skin cells. Image courtesy of Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development at The Rockefeller University.