AH&MRC profile: Elaine Fuchs

As a PhD student in the late 1970s, Elaine Fuchs was fascinated by the ability of laboratory-grown human epidermal keratinocytes to multiply and cover Petri dishes with sheets of new skin.

The discovery of the first adult stem cells was still two decades away, but Fuchs was already asking the right questions. In what part of the skin did the self-renewing cells reside, and how did they continually replenish the community of different cell types that protect the body against life’s hard rain of physical and biological insults?

And how are those cellular communities rapidly redirected from routine maintenance to the urgent business of wound repair in regions where the skin has been breached?

Fuchs, from New York’s Rockefeller University, is a plenary speaker at the 2008 Australian Health & Medical Research Congress in Brisbane. She is not a clinical researcher but has spent most of her career working at the interface between the laboratory and the clinic.

Fuchs has made it her life’s mission to develop a fundamental understanding of how skin evolved, how it is organised, and how it works, at the genetic, cellular and systemic level.

“I was a graduate student at Princeton University, trained in chemistry, biochemistry, and I had been working on bacteria,” she says. “I decided I really wanted to work in an area that, even though it was fundamental science, could be applied to biomedicine.

“I was interested in understanding cells divide and differentiate, and what controls the balance of cell types, and if I wanted to eventually apply my understanding of the biology of the process to a clinical setting I needed to understand what processes were normal before I could study what was abnormal.”

To understand the molecular processes underlying the capacity of cells and tissues to self-renew, Fuchs needed a good cell-culture method. A literature search was largely unhelpful – “It‘s still the case that there are very few culture systems for maintaining and propagating adult stem cells,” she says.

“Although I knew little about skin at the time, I chose skin cells as a model system. It’s still an extraordinary capability of skin stem cells that they can be grown in culture and then grafted on to a human or animal.

“It’s now possible to propagate many types of stem cells in culture but our understanding of the stem cell biology of the skin and the haemopoietic system have been evolving for more than 30 years, when the existence of those other adult stem cells was not even realised.”

Fuchs has made important discoveries about the genetic basis of skin disorders, including blistering diseases and skin cancers, and helped develop techniques for maintaining and propagating epidermal keratinocytes – now recognised as skin stem cells – to grow new skin for patients with severe burns.

“Today, most burns trauma units in the world’s major hospitals have cell-culture laboratories associated with them, and they’ve proven to be very successful in the clinical setting of burns treatment. It’s a great success story, given that 30 years ago we had no idea that skin stem cells existed – nobody called them stem cells.

“They were effectively nothing more than cells that were able to self-renew, and produce new tissue on a long-term basis – we didn’t realise that out ability to grow epidermal keratinocyties and graft them back onto the epidermis was actually a test of ‘stemness’.”

---PB--- Hair-follicle stem cells

The advent of knockout transgenic mouse technology in the late 1980s transformed biomedical research. Fuchs says it has allowed her research team to tease apart the contributions of individual genes to skin development, and understand the genetic defects involved in certain skin disorders.

“There are definitely individual populations of skin stem cells. We’ve been studying the niches where they reside in the skin, and their capabilities.

“We’ve focused on stem cells of the skin epithelium – the epidermis, hair follicles, sweat glands and sebaceous glands. Sweat glands were a challenge to study in their mouse model, because mice have sweat glands only on their paws.

“We’ve isolated and characterised stem cells for hair follicles – when skin is grown for burn grafts, it lacks sweat and hair follicles, because stem cells from the basal layer of the epidermis don’t form these cells.”

Fuchs says hair-follicle stem cells appear to be the master cells, capable of giving rise to other skin stem cells.

“Epidermal stem cells can repair the epidermis, but we’ve shown that, in young skin, hair-follicle stem cells are the major source of the cells involved in wound repair.”

Hair follicles and sweat glands are epidermal appendages, and Fuchs’ group is now exploring whether they are also the source of stem cells that form sweat glands.

“It’s an interesting possibility,” she says. “Natural selection may have put the master population of stem cells in the appendages of the skin epidermis because these structures extend much deeper into the skin structure.”

The epidermis, which forms the body’s outer seal, is about the thickness of cellophane. If it contained the master cells, they would be at risk of loss through injury.

Using differential expression systems in keratinocytes, Fuchs and her colleagues have identified the underlying mutations in several skin-blistering disorders, including epidermolytic hypkeratosis (EDHK).

Fuchs says highly cross-linked keratin fibres give the surface layers of skin their mechanical strength, but in EDHK, mutations in two genes, keratin 1 and keratin 2 weaken the suprabasal layers, which break down under stress. Normal wound-repair processes then cause severe crusting of the skin.

---PB--- Stem cell therapy

Fuchs says a class of autosomal dominant skin disorders called icythyoses, which give the skin a scaly, tiled appearance, may be good candidates for stem cell therapy. The therapy would involve taking stem cells from the patients, inserting a normal variant of the defective gene, then culturing them to produce skin for skin grafts.

She says the treatment would not be suitable for entirely replacing the skin, but it could be used on the face, and in the flexural regions like the backs of the knees and inside the elbows.

“A colleague at Stanford, Paul Khavari, is using keratin promoters we cloned to experiment with this approach. We’ve been very interested in hair-follicle stem cells as potential cells not only for hair replacement, but also for improving skin grafts for burns, because current skin grafts do not form appendages like hair follicles and sweat glands.

“We’ve veered away from the idea of stem cell replacement therapies, towards trying understand what controls the stem cell biology of hair cells, and what the control mechanisms are.

“Stem cell transplants would be like trying to grow a forest by planting individual seeds. If we could understand the mechanisms of stem cell activation, then we could render stem cells amenable to novel drug therapies.”

The team has been making good progress – in 2004 they published the first transcriptional profile of hair follicles, and confirmed their multi-potency.

“We’ve identified transcription-factor complexes, and traced the embryonic development of hair-follicle cells. We’ve shown that Wnt signals control the replication and recycling processes. We’re now at the point of developing broader screens for stem cell activation.”