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Vitamin A May Play a Central Role in Stem Cell Biology and Wound Repair

Longevity By Nature

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Retinoic acid, the active state of vitamin A, appears to regulate how stem cells enter and exit a transient state central to their role in wound repair.

When a child falls off her bike and scrapes her knee, skin stem cells rush to the rescue, growing new epidermis to cover the wound. But only some of the stem cells that will ultimately patch her up are normally dedicated to replenishing the epidermis that protects her body. Others are former hair follicle stem cells, which usually promote hair growth but respond to the more urgent needs of the moment, morphing into epidermal stem cells to bolster local ranks and repair efforts. To do that, these hair follicle stem cells first enter a pliable state in which they temporarily express the transcription factors of both types of stem cells, hair and epidermis.

Now, new research demonstrates that once stem cells have entered this state, known as lineage plasticity, they cannot function effectively in either role until they choose a definitive fate. In a screen to identify key regulators of this process, retinoic acid, the biologically active form of vitamin A, surfaced as 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,” said 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 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,” explained 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.”

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 said. 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 nuance did not stop there. Fuchs and colleagues also demonstrated that retinoic acid levels must fall for hair follicle stem cells to participate in wound repair—if levels are too high, they fail to enter lineage plasticity and can’t repair wounds—but if the levels are too low, the stem cells focus too heavily on wound repair, to the expense of hair regeneration.

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

For more information, www.rockefeller.edu.