Maintaining Balance in the Skin with Cellular Mechanics

The balance between cell differentiation and division is of great importance. While too much differentiation leads to loss of stem cells and premature aging, too many cell divisions leads to skin cancer. Yesterday, a study was published in Nature Communications that investigated how polarity regulators like the cell polarity protein Par3 control cellular mechanics in the skin.

The skin serves as a crucial barrier to the outside world. Its task is not only to keep pathogens or toxic chemicals out of the body but also to keep water inside and maintain hydration. In order to function properly, the skin epidermis needs to maintain a balance between the cells it sheds off and the new cells that replenish the lost ones. Skin stem cells are responsible for the self-renewing capacity of the skin.

In a previous study, the researchers showed that inactivation of the polarity protein Par3 resulted in a decline of stem cells, impaired skin homeostasis, and premature skin aging. But the underlying mechanisms were still unclear. In the new study, the team showed that Par3 directly influences homeostasis in the skin by controlling mechanical properties in the main skin epithelial cells—keratinocytes.

The recent work started with two separate approaches. “We realized that inactivating Par3 leads to failures in cell divisions, resulting in DNA damage responses,” says co–first author Martim Dias Gomes.

At the same time, his colleague and co–first author, Soriba Letzian, was working on another project. “We challenged mouse skin with UV light—but observed an unexpected DNA damage response already in absence of the harmful light when Par3 was missing,” Letzian said. “That was the moment we realized that the DNA damage response and the aberrant cell divisions might be tightly linked.”

As they now show, Par3 is an important regulator of contractility of keratinocytes, which is required to maintain the accuracy of cell division events. The absence of Par3 leads to mitotic errors, causing an alert signal and a cascade of DNA damage responses that then fuel premature differentiation and, potentially, the skin stem cell decline. The findings thus revealed that core polarity proteins like Par3 steer mechanochemical networks that are essential to keep a healthy self-renewal capacity.

Image: A digitally processed micrograph of mouse skin and hair follicles, with DNA damage (green) in the skin epithelium, including the hair follicle stem cells (purple). Blue depicts cell nuclei. Image courtesy of Martim Dias Gomes.