Elaine Fuchs, Ph.D., studies stem cells from mouse skin to understand normal skin biology. She shared her research during a NIEHS Distinguished Lecture Series talk on March 20. Carmen Williams, M.D., Ph.D., deputy chief of the NIEHS Reproductive and Developmental Biology Laboratory, hosted the seminar.

Fuchs said she became interested in studying skin as a graduate student after hearing a lecture by physician-scientist Howard Green, M.D. Green, who was at the Massachusetts Institute of Technology at the time, could take a piece of human skin and culture the cells endlessly without their losing the ability to become viable skin tissue (see sidebar). Fuchs was fascinated and eventually joined his lab as a postdoctoral fellow.

'When we forced hair cycle divisions over and over again, the stem cells run out of gas,' Fuchs said. 'We don’t have an endless supply of hair follicle stem cells.' (Photo courtesy of Steve McCaw)

The inactive-active transition

In her current position with the Howard Hughes Medical Institute and as Rebecca C. Lancefield Professor at The Rockefeller University, Fuchs uses mouse hair follicles to understand stem cells. Because stem cells are located at the base of hair follicles and drive hair growth, she said hair follicles are the perfect system for examining how stem cells transition from a dormant, or quiescent, state to an activated state.

According to Fuchs, the dermis, or middle layer of the skin, has small extensions called dermal papillae that connect the outer epidermal layer of skin with the blood supply. The dermal papillae also crosstalk with the stem cells at the base of the hair follicle, providing activating cues that shift stem cells into a tissue-generating mode.

'Although active hair growth goes on for three weeks in the mouse, there’s only a couple of days very early on where hair follicle stem cells become active and proliferate,' Fuchs said. 'Thereafter, they remain quiescent.'

Future therapies for skin cancer

Williams is also head of the NIEHS Reproductive Medicine Group. (Photo courtesy of Steve McCaw)

The Fuchs lab also used the mouse model to examine squamous cell carcinoma, one of the most common types of skin cancer. The Cancer Genome Atlas identifies thousands of coding mutations that occur more than once in different patients, but Fuchs wondered which of these gene mutations were drivers of cancer.

So she and her lab performed gene knockdowns on mouse skin cells and looked at the effects on oncogenic stem cells of the skin versus normal stem cells of the skin. Their goal was to develop therapies that specifically affect cancer stem cells.

Skin — an excellent system

During her hour-long seminar, Fuchs demonstrated why skin stem cells are a good model system to study, citing other important findings that. For instance, regardless of whether stem cells are cancerous or normal, the key genes that control them are regulated by super enhancers.

To cope with inflammatory or oncogenic stress, stem cells survive by adjusting to their new microenvironments, which involves transcriptional, translational, and microenvironment changes.

Finally, skin stem cells are similar to immune cells, in that both produce memory cells that allow the organism’s immune system to remember the pathogen for faster antibody production in the future.