Before the hair follicle stem cells can do that, they must first enter a pliable state (lineage plasticity) in which they temporarily express transcription factors of both types of stem cells, hair and epidermis. Once stem cells have entered lineage plasticity, they are not able to effectively function in either role until they choose a definitive fate.
“Our goal was to understand this state well enough to learn how to dial it up or down,” says Rockefeller’s Elaine Fuchs. “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 can be observed in multiple tissues as a natural response to wounds and it is also an unnatural feature of cancer. Lineage plasticity “can act as a double-edged sword,” explains Matthew Tierney, lead author on the paper and an NIH K99 “pathway to independence” postdoctoral awardee in the Fuchs lab. “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.”
For this study from Rockefeller University published in the journal Science, small molecules were screened for their ability to resolve lineage plasticity in cultured mouse hair follicle stem cells in conditions mimicking wounded states. The researchers found that genetic, dietary, and topical interventions that boosted or removed retinoic acid (a biologically active form of vitamin A) from mice confirmed its role in balancing how stem cells respond to skin injuries and hair regrowth. Retinoids were found not to operate on their own, interplaying with signaling molecules to influence whether the stem cells should maintain quiescence or engage in regrowing hair.
According to the team, retinoic acid levels must fall for the hair follicle stem cells to participate in wound repair. If the levels are too high, they do not enter lineage plasticity and will not be able to repair wounds, and if the levels are too low, the stem cells focus too much on wound repair at the expense of hair regeneration.
“This may be why vitamin A’s effects on tissue biology have been so elusive,” Fuchs says.
“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 says.
“When you eat a carrot, vitamin A gets stored in the liver as retinol where it is sent to various tissues,” Fuchs says. “Many tissues that receive retinol and convert it to retinoic acid need wound repair and use lineage plasticity, so it will be interesting to see how broad the implications of our findings in skin will be.”
“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.”
“It’s possible that suppressing lineage plasticity can improve prognoses,” Fuchs says. “This hasn’t been on the radar until now. It’s an exciting front to now investigate.”
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