Developmental Biology - Skin|
Skin Cells Continuously Meet a Swift Death
Skin cells swiftly convert into flat, dead squames cells — that provide a tight seal against the outside world - or not...
Skin is our body's best defense against pathogens and other external threats. Its outermost layer is maintained through a remarkable transformation into squames — flat, dead cells that form a tight seal against the outside world.
"Throughout our lifetime, squames are continually being shed from our skin surface and replaced by inner cells - moving outward. Now we've identified the mechanism that allows skin cells to sense change in their environment and quickly deploy instructions that drive squame formation."
Elaine Fuchs PhD, Rockefeller's Rebecca C. Lancefield Professor, Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA.
Conducted in mice and described in the journal Science, the research provides new insight into how errors in this mechanism could lead to skin conditions like atopic dermatitis and psoriasis.
Like Oil and Vinegar
The skin's epidermis consists of an inner layer of stem cells that periodically stop dividing and begin moving outward, toward the body's surface. As the cells transit, they face increasing extremes such as variations in temperature. Approaching the outer surface, the cells' nuclei and organelles are suddenly lost in a dramatic transformation and become squames.
Felipe Garcia Quiroz, Fuchs' postdoctoral fellow, noticed that just before skin cells turn into squames — dark protein deposits appear. This is called phase separation. A phenomenon occuring when liquids with mismatched properties separate.
Quiroz and colleagues suspected that in skin cells, the dark protein deposits known as keratohyalin granules, carry molecular signals prompting cells to quickly flatten and die. To test this idea, researchers developed a phase separation sensor, a biomolecule that emits green light when keratohyalin granules form, then dissipates when these granules disassemble. With this tool, they identified that the protein filaggrin, known to mutate in some skin conditions, plays a key role in granule formation.
"If filaggrin is not functioning properly, phase separation fails to occur, skin lacks keratohyalin granules and cells can no longer transform in response to environmental triggers."
Felipe Garcia Quiroz PhD, Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA./span>
Therefore, filaggrin and phase separation are tied into the formation of the outer layers of skin. This finding sheds new light on the underlying causes of skin conditions linked to mutations in filaggrin. For example, when Quiroz engineered filaggrin proteins mimicking mutations associated with atopic dermatitis, skin cells no longer form normal granules.
"We suspect the lack of phase separation contributes to defects in building a skin barrier, resulting in the inflamed, cracked skin seen in these conditions. Most treatments thus far focus on suppressing the immune system. But our findings suggest we should be looking more closely into the cellular barrier itself."
Elaine Fuchs PhD
Fuchs hopes their work will open up entirely new avenues for developing skin treatments for filaggrin-linked skin diseases.
At the body surface, skin’s stratified squamous epithelium is challenged by environmental extremes. The surface of the skin is composed of enucleated, flattened surface squames. They derive from underlying, transcriptionally active keratinocytes that display filaggrin-containing keratohyalin granules (KGs) whose function is unclear. Here, we found that filaggrin assembles KGs through liquid-liquid phase separation. The dynamics of phase separation governed terminal differentiation and were disrupted by human skin barrier disease–associated mutations. We used fluorescent sensors to investigate endogenous phase behavior in mice. Phase transitions during epidermal stratification crowded cellular spaces with liquid-like KGs whose coalescence was restricted by keratin filament bundles. We imaged cells as they neared the skin surface and found that environmentally regulated KG phase dynamics drive squame formation. Thus, epidermal structure and function are driven by phase-separation dynamics.
Felipe Garcia Quiroz, Vincent F. Fiore, John Levorse, Lisa Polak, Ellen Wong, H. Amalia Pasoll and Elaine Fuchs.
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Formation of GREEN droplets of a phase separation sensor indicates the formation ofkeratohyalin granules
which drive the rapid transformation of skin cells into squames.
CREDIT Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of
Mammalian Cell Biology and Development, The Rockefeller University, New York.