Hair follicle stem cells (green) recruit and expand (white) and help repair the skin barrier by differentiating into epidermal lineages (red).
If a child falls off a bike and scrapes his knee, skin stem cells come to the rescue and grow new epidermis to cover the wound. However, only some of the stem cells that will eventually repair her are usually dedicated to replenishing the epidermis that protects her body. Others are former hair follicle stem cells, which normally promote hair growth, but which transform into epidermal stem cells to address more urgent needs at the moment, strengthening local ranks and performing repair efforts. Masu. To do so, these hair follicle stem cells first enter a flexible state in which they transiently express transcription factors for both hair and epidermal stem cell types.
Now, new research shows that once stem cells enter this state known as lineage plasticity, they are unable to function effectively in either role until they choose their final fate. In a screen to identify key regulators of this process, retinoic acid, the biologically active form of vitamin A, emerged as a surprising rheostat. This finding highlights lineage plasticity with potential clinical implications.
“Our goal was to understand this condition so well that we could learn how to dial it up or dial it down,” says Rockefeller’s Elaine Fuchs. “We now have a path to understanding skin and hair diseases and preventing cell lineage plasticity from contributing to tumor growth.”
indecisive stem cells
Lineage plasticity has been observed in multiple tissues as a natural response to injury and an unnatural feature of cancer. However, because the outer layer of the skin is exposed to persistent abuse, mild skin damage is the perfect place to study this phenomenon. And when a scratch or abrasion damages the epidermis, hair follicle stem cells are the first responders.
Fuchs and his colleagues began looking more closely at lineage plasticity because it “could act as a double-edged sword,” said Fuchs, lead author of the paper and an NIH K99 “Path to Independence” postdoctoral fellow in the Fuchs lab. Matthew Tierney, winner of the award, explains: “This process is necessary to redirect stem cells to the parts of the tissue where they are most needed, but if left unchecked, it can leave those same tissues vulnerable to chronic reparative conditions and even some types of cancer. There is a possibility that it will.”
To better understand how the body regulates this process, Fuchs and her team conducted a small study on the ability of cultured mouse hair follicle stem cells to resolve lineage plasticity under conditions that mimic wound conditions. The molecules were screened. They found that retinoic acid, a biologically active form of vitamin A, is essential for these stem cells to exit lineage plasticity and then be induced to differentiate into hair cells or epidermal cells in vitro. I was surprised to discover this.
“Through studies, first in vitro and then in vivo, we have discovered previously unknown effects on vitamin A, a molecule long known to have powerful but often mysterious effects on the skin and many other organs. “We discovered features that weren’t available before,” Fuchs said. The researchers found that genetic, dietary, and topical interventions that increase or remove retinoic acid from mice all support the role of balancing how stem cells respond to skin damage and hair regeneration. I discovered that there is. Interestingly, retinoids do not work on their own. Interactions with signaling molecules such as BMPs and WNTs influence whether stem cells remain quiescent or actively participate in hair regeneration.
The nuances didn’t stop there. Fuchs et al. also demonstrated that retinoic acid levels need to decrease for hair follicle stem cells to participate in wound repair. If the levels are too high, they will not enter lineage plasticity and will not be able to repair the wound, but if the levels are too low, the stem cells will focus too much on wound repair, at the expense of hair regeneration.
“This may be why the effects of vitamin A on tissue biology are so elusive,” Fuchs says.
Vitamin A plays a key role
One consequence of the biology of retinol remaining unclear for so long is that the application of retinoids and vitamin A has long produced confusing results. Topical retinoids are known to stimulate hair growth in scars, but excess retinoids have been shown to interfere with the hair cycle and cause hair loss. Both positive and negative effects of retinoids on epidermal repair have been documented through various studies. This study provides greater clarity by casting retinoids in a more central role in controlling both hair follicles and epidermal stem cells.
“By defining the minimal requirements needed to form mature hair cell types from stem cells in vitro, this study has the potential to change the way we approach research in hair biology.” Tierney says.
It is not yet known how retinoids affect other tissues. “When you eat carrots, vitamin A is stored as retinol in your liver, where it is sent to various tissues,” Fuchs says. “Many tissues that receive retinol and convert it to retinoic acid require wound repair and take advantage of cell lineage plasticity, so it will be interesting to see how broadly our findings in skin will have an impact. Sho.”
Fuchs’ lab is also interested in how retinoids affect lineage plasticity in cancer, particularly squamous cell carcinoma and basal cell carcinoma. “Cancer stem cells never make the right choice; they’re always doing something outlandish,” Fuchs says. “As we studied this condition in different types of stem cells, we began to realize that when cell lineage plasticity is left unchecked, it is a major cause of cancer.”
Basal cell carcinomas have relatively less lineage plasticity and are much less aggressive than squamous cell carcinomas. If future studies prove that suppressing lineage plasticity is key to controlling tumor growth and improving outcomes, retinoids could play an important role in the treatment of these cancers.
“Suppressing lineage plasticity may improve prognosis,” Fuchs says. “This hasn’t gotten any attention until now. It’s an exciting frontier to investigate now.”
