A study discovered a new underlying mechanism with stem cells causing the hair to turn gray, which could lead to potential treatment. Hair follicles contain several different types of cells, including melanocyte stem cells that generate cells that produce the pigment melanin responsible for hair color.
A new study in mice shows that these melanocyte stem cells migrate between two sites in the hair follicle during each cycle of hair growth and shedding— from a site where they produce the pigment for hair color to another where they produce stem cells.
The study found that aging results in a greater portion of these melanocyte stem cells getting stuck at the site where they produce stem cells, which leaves a smaller portion of stem cells to generate melanin-producing cells, resulting in the graying of hair.
These results provide insight into the mechanisms underlying the graying of hair and could help devise treatments for the treatment of hair graying.
Hair follicles, the structures that produce hair, undergo several cycles of growth over an individual’s lifetime. The increase in the number of follicle growth cycles with aging is associated with deficits in melanocyte stem cells , the stem cells residing in the follicle that can form hair pigment-producing melanocytes. These deficits are thought to lead to graying of hair.
Melanocyte stem cells are found in two distinct locations at the base of each hair follicle. In one of the locations—called the bulge— these McSCs undergo self-renewal to maintain a population of immature stem cells. In the other location—called the hair germ area—McSCs can differentiate to form melanocytes that produce melanin pigment for hair.
It was previously thought that once McSCs differentiated into melanocytes, this process was irreversible.
Instead, a recent study published in Nature suggests that the McSCs can migrate back and forth between the two aforementioned locations, differentiating to produce hair pigment-producing melanocytes in the hair germ area and then translocating to the bulge and dedifferentiating to ensure the maintenance of an adequate supply of stem cells.
In other words, during each growth cycle, the McSCs can differentiate into a pigment-producing partially differentiated state and then revert back to an undifferentiated state.
The study also showed that the migration of the cells between these regions is disrupted with repeated hair follicle growth cycles. This results in fewer stem cells that can develop into pigment-producing melanocytes, thus leading to hair graying.
The study’s author Dr. Mayumi Ito,Ph.D., a cell biologist at New York University, said, “[Our] analysis revealed melanocyte stem cells are more dynamic/mobile than previously thought. We revealed that as melanocyte stem cells move within the hair follicle, stem cells can reversibly alter cell state from immature to mature state, and this reversibility is critical for the proper maintenance of these stem cells.”
Dr. Ito also noted, “The study is built upon previous studies showing that maintaining healthy melanocyte stem cells is the key to preserving hair color. Our study suggests that melanocyte stem cells are mobile but can start the regeneration of hair melanocytes only when they are present in a specific area within the hair follicle (hair germ compartment). Our study also suggests that melanocyte stem cell localization may be altered during the course of aging. Moving melanocytes to a proper location within the hair follicle may help prevent hair greying.”
Stem cells’ role in hair growth phases
Each strand of hair consists of the outer visible part called the shaft and the root that lies beneath the surface of the skin. The root of the hair is surrounded or encased by the hair follicle, which is responsible for promoting hair growth. The hair follicle also influences the texture and color of hair.
Among the wide variety of cells present in the hair follicle include stem cells. Stem cells in the body are responsible for the regeneration of tissue in the body and can differentiate to form an array of specialized cells.
Specifically, the division of a stem cell can result in the formation of identical daughter stem cells and/or cells that can differentiate to assume different fates. This differentiation of stem cells to a cell type that performs a specific function is thought to be irreversible.
The stem cells in the hair follicle generate the cells to help regenerate hair follicle cells and facilitate hair growth. During a person’s lifetime, each hair follicle undergoes several growth cycles that consist of three phases.
Anagen refers to the growth phase that can last between two to six years and involves the division of cells in the hair follicle, leading to the elongation of the hair shaft.
The growth phase is followed by a short transitional phase, catagen, that lasts a few weeks and involves shrinkage of the hair follicle and slowing of hair growth.
The subsequent phase is called the resting phase or telogen, which lasts three to four months and involves the cessation of growth and shedding of old hair, followed by the initiation of a new growth phase.
Cells that compose the hair follicle and produce keratin are generated by hair follicle stem cells. In contrast, the melanocytes that produce melanin, the pigment responsible for hair color, are generated by the differentiation of melanocyte stem cells (McSCs).
These McSCs are present at two distinct locations during the telogen phase. This includes McSCs present in a transitory structure called the hair germ area. The hair germ area also contains hair follicle stem cells and plays an important role in hair elongation during the growth phase.
Above the hair germ area of the hair follicle lies a region called the bulge, which also contains McSCs. The bulge area is known as the stem cell compartment and is thought to be necessary for maintaining a reserve stem cell population.
While the bulge area potentially serves as the stem cell compartment, the melanocyte stem cells in the hair germ area differentiate to form mature melanocytes that produce pigment for hair during the growth or anagen phase.
In the present study, the researchers examined how the McSCs in the bulge and hair germ areas differed in their function and ability to proliferate.
Transforming hair pigment cells
The researchers found that McSCs were mostly localized to the hair germ area rather than the bulge before the onset of the growth phase. These McSCs present in the hair germ compartment largely contributed to the population of daughter McSCs and differentiated melanocytes. Researchers found few McSCs in the bulge area, highlighting the importance of hair germ McSCs in producing both mature differentiated melanocytes and maintaining the McSC population.
In addition, the researchers found that the differentiation of hair germ McSCs into pigment-producing mature melanocytes in the bulb during the growth phase was irreversible, and these melanocytes died by the end of the growth phase. These mature melanocytes did not show stem cell markers.
The proliferation of hair germ McSCs also produced identical daughter McSCs that were able to differentiate into an intermediate differentiated state in the hair germ area. These daughter McSCs expressed both stem cell markers and pigment genes during the early-mid growth phase.
Moreover, these hair germ McSCs could migrate to the bulge during anagen. In the bulge, these McSCs dedifferentiated to maintain the stem cell population. These undifferentiated McSCs present in the bulge during the anagen phase and then migrated back to the hair germ area by the next telogen phase.
In other words, these findings suggest that McSCs—unlike other stem cells—are able to move from an undifferentiated state to a differentiated state and back.
This means instead of distinct stem cell populations occupying the bulge and hair germ compartments, the McSCs travel between these sites and have the ability to perform the functions of both self-renewal and producing differentiated, mature melanocytes.
Melanocyte stem cells can dedifferentiate
Dr. Rui Yi,Ph.D., a professor of dermatology at Northwestern University, noted that it had been shown that specialized cells derived from stem cells can undergo dedifferentiation when exposed to a specific cell culture environment. However, there is limited evidence of the dedifferentiation of stem cells in living organisms.
“People generally think stem cells maintain their stemness by self-renewal, but they can also differentiate to form different cell types. Typically, we think that this process of differentiation is irreversible. For example, hematopoietic stem cells can differentiate into different blood cells, including T cells and B cells. These cells will normally never revert back,” Dr. Yi said.
“This is a demonstration that the tissue stem cell, in this case, melanocyte stem cells, can definitely dedifferentiate. The study showed that melanocyte stem cells can differentiate, and once they go into the appropriate microenvironment, they can dedifferentiate,” he explained.
Previous studies have shown that the signaling pathway activated by the protein Wnt can influence the differentiation of McSCs. The findings from the present study suggested that the protein Wnt expressed by epithelial cells in the bulb activated the Wnt signaling pathway in hair germ McSCs, causing them to differentiate.
Also, lower levels of Wnt were present in the bulge and the downregulation of the Wnt signaling pathway in McSCs led to their dedifferentiation into a stem cell state.
These results suggest that the Wnt pathway plays an important role in the regulation of the differentiation and dedifferentiation of the McSCs.
Plucking hair to speed up aging
Previous studies have shown a more rapid age-associated decline in the regenerative capacity of McSCs than that observed in follicle stem cells. As a result, the follicle stem cells continue to produce cells that facilitate hair elongation but in the absence of adequate pigment-producing melanocytes. This results in graying of hair with aging.
In the present study, the researchers examined whether a change in the distribution of McSCs in the bulge and hair germ area could explain the graying of hair. To assess how aging could lead to the graying of hair, the researchers hastened the aging process by plucking the hair of mice during each telogen phase.
They found that the number of McSCs in the bulge stem cell compartment increased from 10% to 50% after hair plucking. This was due to fewer McSCs returning to the hair germ compartment from the bulge stem cell compartment during the telogen phase.
Moreover, unlike the hair germ McSCs that can proliferate to form both differentiated mature melanocytes and progeny McSCs, McSCs in the bulge area were mostly quiescent and only contributed to the self-renewal of McSCs.
In other words, the McSCs in the bulge mostly contribute to the maintenance of the stem cell population through self-renewal and do not produce differentiated pigment-producing melanocytes. Thus, the accumulation of hair germ McSCs in the bulge with aging may lead to a lower proportion of stem cells returning to the hair germ area, where they could produce the melanin pigment for hair.
Dr. Yi noted that these experiments were conducted in mice, and further research is needed to examine whether these findings can be replicated in humans.
“There’s obviously a difference between mice and humans. So to what extent this finding can directly translate into human health, I am not sure. That’s what the author and the entire field are still working out,” Dr. Yi said.
– Deep Shukla
