Although lineage plasticity is integral to the stem cell stress response, this transient state is poorly understood. In a screen to identify key regulators of this process, Rockefeller University researchers found that retinoic acid, the biologically active form of Vitamin A, was a surprising rheostat. The findings shed light on lineage plasticity, with potential clinical implications.
“Our goal was to understand this state well enough to learn how to dial it up or down,” says Elaine Fuchs, senior author of the paper published in Science. “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.”
Lineage plasticity has been observed in multiple tissues as a natural response to wounding and an unnatural feature of cancer. But minor skin injuries are the best place to study the phenomenon, because the skin’s outer layers are subject to perpetual abuse. And when the scratches or abrasions damage the epidermis, hair follicle stem cells are the first responders.
Fuchs and colleagues began to look more closely at lineage plasticity because it, “can act as a double-edged sword,” explains Matthew Tierney, lead author on the paper. “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.”
To better understand how the body regulates this process, Fuchs and her team screened small molecules for their ability to resolve lineage plasticity in cultured mouse hair follicle stem cells, under conditions that mimicked a wound state. They were surprised to find that retinoic acid, a biologically active form of vitamin A, was essential for these stem cells to exit lineage plasticity and then be coaxed to differentiate into hair cells or epidermal cells in vitro.
“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,” Fuchs says. The team found that genetic, dietary, and topical interventions that boosted or removed retinoic acid from mice all confirmed its role in balancing how stem cells respond to skin injuries and hair regrowth. Interestingly, retinoids did not operate on their own: their interplay with signaling molecules such as BMP and WNT influenced whether the stem cells should maintain quiescence or actively engage in regrowing hair.
The Fuchs lab is also interested in how retinoids impact lineage plasticity in cancer, particularly squamous and basal cell carcinoma. “Cancer stem cells never make the right choice—they are always doing something off-beat,” Fuchs says. “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.