Certain stem cells have a unique ability to move between growth compartments in hair follicles, but they get stuck as people age and lose their ability to mature and maintain hair color, a new study shows.
Led by researchers at New York University’s Grossman School of Medicine, the new work focused on skin cells in mice and also in humans called melanocyte stem cells, or McSCs. Hair color is controlled by whether non-functional but continuously multiplying McSC clusters within hair follicles receive the signal to become mature cells that produce the protein pigments responsible for color.
Published in the journal Nature online on April 19, the new study showed that McSCs are remarkably plastic. This means that during normal hair growth, these cells continually move back and forth on the maturation axis as they transit between compartments of the developing hair follicle. It is within these compartments that McSCs are exposed to different levels of protein signals that influence maturity.
Specifically, the research team found that McSCs transform between their most primitive stem cell state and the next stage of their maturation, the transit amplification state, and depending on their location.
The researchers found that as hair ages, falls out, and then repeatedly grows back, an increasing number of McSCs get stuck in the stem cell compartment called the bulge of the hair follicle. They remain there, do not mature to the transit-amplified state, and do not travel back to their original location in the germinal compartment, where WNT proteins would have pushed them to regenerate into pigment cells.
"Our study adds to our basic understanding of how melanocyte stem cells function to dye hair," said the study’s principal investigator, Qi Sun, PhD, a postdoctoral fellow at NYU Langone Health. "The newly discovered mechanisms raise the possibility that the same fixed position of melanocyte stem cells may exist in humans. If so, it presents a potential avenue to reverse or prevent graying of human hair by helping stuck cells move again." between the developing hair follicle compartments".
The researchers say that McSC plasticity is not present in other self-renewing stem cells, such as those that make up the hair follicle itself, which are known to move in a single direction along a set timeline as they mature. For example, hair follicle cells that amplify transit never return to their original stem cell state. This helps partly explain why hair can continue to grow even when its pigmentation fails, Sun says.
Previous work by the same NYU research team showed that WNT signaling was needed to stimulate McSCs to mature and produce pigment. That study also showed that McSCs were billions of times less exposed to WNT signaling in the hair follicle than in the hair germ compartment, which is located directly beneath the bulge.
In the latest experiments on mice whose hair was physically aged by hair removal and forced regrowth, the number of hair follicles with McSCs lodged in the follicle bulge increased from 15% before hair removal to almost half after forced aging. These cells remained unable to regenerate or mature into pigment-producing melanocytes.
The researchers found that the stuck McSCs ceased their regenerative behavior as they were no longer exposed to much WNT signaling and therefore their ability to produce pigment in new hair follicles, which continued to grow.
In contrast, other McSCs that continued to move back and forth between the follicle bulge and the hair germ maintained their ability to regenerate as McSCs, mature into melanocytes, and produce pigment throughout the two-year study period.
"It is the loss of chameleon function in melanocyte stem cells that may be responsible for aging and loss of hair color," said the study’s principal investigator, Mayumi Ito, PhD, professor in the Ronald Department of Dermatology. O. Perelman and the Department of Cell Biology at NYU Langone Health.
"These findings suggest that melanocyte stem cell motility and reversible differentiation are key to maintaining healthy, colored hair," said Ito, who is also a professor in the Department of Cell Biology at NYU Langone.
For the study, the researchers used recent 3D intravital imaging and scRNA-seq techniques to track cells in near real time as they aged and moved within each hair follicle.
Funding for the study was provided by National Institutes of Health grants P30CA016087, S10OD021747, R01AR059768, R01AR074995, and U54CA263001; and Department of Defense grants W81XWH2110435 and W81XWH2110510.
