Impaired Melanocyte Stem Cell Migration Implicated in Hair Graying

Reading around the present state of research into the aging of skin and hair provides interesting insights into the gap between knowledge and understanding in complex biological systems. At this point, there is no complete understanding as to how skin and hair age, even while there is an enormous amount of data on the cellular biology and behavior on all of the different cell types involved. This is a microcosm of the bigger picture of aging in general: while well-researched lists of fundamental forms of damage and change exist, showing exactly how those processes interact to produce the decline of a larger system remains a work in progress. So while researchers understand a great deal about the building blocks involved in hair turning gray with age, much remains to be accomplished when it comes to describing how those building blocks lead to the outcome.

This is why it is important to advocate for more attention to be given to intervention, in parallel with observation. The state of the art in biotechnology allows the research community to repair the forms of damage thought to cause aging. We should do that, and not wait around for greater understanding of a highly complex system to emerge from observation. Further, it is likely that repair therapies will provoke that greater understanding, at least to the degree that they are successful. See, for example, the greatly increased understanding of cellular senescence in aging that has followed the development of senolytic treatments that selectively destroy these cells to produce rejuvenation in animal models.

Today's research materials are an example of an incremental advance in the understanding of age-related hair graying, involving a specific behavioral change in stem cells responsible for the production of melanocytes. Because this one of the early issues in aging, occurring quite independently of functional loss elsewhere in the body, it is quite possible that the mechanisms involved will be of little use understanding or intervening in other aspects of aging, but time will tell.

Study Links 'Stuck' Stem Cells to Hair Turning Gray

Certain stem cells have a unique ability to move between growth compartments in hair follicles, but get stuck as people age and so lose their ability to mature and maintain hair color. A new study focused on cells in the skin of mice and also found in humans called melanocyte stem cells, or McSCs. Hair color is controlled by whether nonfunctional but continually multiplying pools of McSCs within hair follicles get the signal to become mature cells that make the protein pigments responsible for color.

This means that during normal hair growth, such cells continually move back and forth on the maturity axis as they transit between compartments of the developing hair follicle. It is inside these compartments where McSCs are exposed to different levels of maturity-influencing protein signals. Specifically, the research team found that McSCs transform between their most primitive stem cell state and the next stage of their maturation, the transit-amplifying state, and depending on their location. The researchers found that as hair ages, sheds, and then repeatedly grows back, increasing numbers of McSCs get stuck in the stem cell compartment called the hair follicle bulge. There, they remain, do not mature into the transit-amplifying state, and do not travel back to their original location in the germ compartment, where WNT proteins would have prodded them to regenerate into pigment cells.

Dedifferentiation maintains melanocyte stem cells in a dynamic niche

For unknown reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems.

Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

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