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Vitamin A’s Role in Skin Influences Wound Repair and Hair Growth

A microscope image showing hair follicle stem cells in the skin's epidermis.
Hair follicle stem cells (green) mobilize and expand (white) to help repair the skin’s barrier by differentiating into epidermal lineages (red). Credit: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development at The Rockefeller University.
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Retinoic acid, a form of vitamin A, can regulate lineage plasticity in skin stem cells, suggests new research from Rockefeller University. The findings, published in Science, could have clinical implications for regenerative medicine, wound healing and even cancer.

Deciding cell fate

When we sustain a cut or a scrape, skin stem cells produce new cells to repair the skin’s outermost layer – the epidermis. But these cells are not alone in helping to replenish the epidermis after wounding. Others, such as hair follicle stem cells, can step up to the plate and morph into epidermal stem cells when needed using a process called lineage plasticity.

During lineage plasticity, hair follicle stem cells enter an intermediate state where they temporarily have the transcription factors of both hair follicle and epidermal stem cells. However, once they enter this state, they must choose a definitive fate before functioning effectively in either role.

Lineage plasticity is a natural response to wounding in multiple tissues. It is best observed in minor skin injuries as the epidermis is relatively easily and frequently damaged. However, lineage plasticity can also be a feature of cancer.

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“The process is necessary to redirect stem cells to parts of the tissue most in need but, if left unchecked, it can leave those same tissues vulnerable to chronic states of repair and even some types of cancer,” explained Dr. Matthew Tierney, a postdoctoral fellow at Rockefeller University and lead author of the study.

Tierney and colleagues investigated how the body controls lineage plasticity, finding that retinoic acid ­– a biologically active form of vitamin A – is a key regulator, with potential clinical implications.

“Our goal was to understand this state well enough to learn how to dial it up or down,” said Prof. Elaine Fuchs, the study’s senior author and Rebecca C. Lancefield Professor at Rockefeller University. “We now have a better understanding of skin and hair disorders, as well as a path toward preventing lineage plasticity from contributing to tumor growth.”

Dual role in hair growth and wound healing

The researchers screened small molecules in lab-grown mouse hair follicle stem cells to find those that could resolve lineage plasticity. They found retinoic acid was essential for stem cells to exit lineage plasticity in vitro and differentiate into either hair or epidermal cells.

“Through our studies, first in vitro and then in vivo, we discovered a previously unknown function for vitamin A, a molecule that has long been known to have potent but often puzzling effects on skin and many other organs,” said Fuchs.

In vivo experiments showed that increasing or decreasing retinoic acid levels using genetic, dietary and topical interventions affected how the stem cells responded to injury and hair regrowth. Additionally, interactions with signaling molecules, such as bone morphogenic protein (BMP) and Wnt, influenced whether stem cells remained dormant or engaged in hair regrowth.

Furthermore, high levels of retinoic acid prevent lineage plasticity and limit wound repair, while low levels promote wound repair at the expense of hair regrowth. However, studies into the role of retinoids have produced confusing results, as topical retinoids can stimulate hair growth in wounds, but in excess can also prevent hair cycling.

“By defining the minimal requirements needed to form mature hair cell types from stem cells outside the body, this work has the potential to transform the way we approach the study of hair biology,” Tierney said.

“This may be why vitamin A’s effects on tissue biology have been so elusive,” Fuchs added.

Potential implications for cancer biology

Fuchs and colleagues are now keen to investigate how retinoids affect lineage plasticity in cancer, particularly in skin cancers such as squamous and basal cell carcinoma. Basal cell carcinomas are less aggressive than squamous cell carcinomas and typically have little lineage plasticity.

“Cancer stem cells never make the right choice – they are always doing something off-beat,” Fuchs said. “As we were studying this state in many types of stem cells, we began to realize that, when lineage plasticity goes unchecked, it’s a key contributor to cancer.”

Therefore, retinoids may have a role to play in cancer treatment if further investigations find that suppressing lineage plasticity can influence tumor growth. “It’s possible that suppressing lineage plasticity can improve prognoses,” Fuchs explained. “This hasn’t been on the radar until now. It’s an exciting front to now investigate.”

Reference: Tierney MT, Polak L, Yang Y, et al. Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices. Science. 2024;383(6687):eadi7342. doi: 10.1126/science.adi7342

This article is a rework of a press release issued by Rockefeller University. Material has been edited for length and content.