Researchers here report their evidence for increased Wnt signaling in hair follicles and skin in older mice to be implicated in the age-related graying of hair. They demonstrate accelerated hair graying through gene therapy to increase Wnt signaling in these cell populations, considering that it produces exhaustion in the cell populations responsible for hair pigmentation. It remains to be seen as to whether the reverse effect can be produced via suppression of this pathway in older animals.
Aging is a physiological process associated with progressive structural and functional declines of tissues and organs. The hair follicle is a mini-organ that undergoes repetitive cyclic regeneration, thus supplying an excellent model for aging-associated disorders. Typical hair follicle aging phenotypes can be observed but not limited to several signs, such as irreversible hair loss, hair thinning and graying.
Regenerative hair cycling process in a single hair follicle consists of three consecutive phases including growth phase (anagen), regression phase (catagen) and resting phase (telogen). Hair stem cell activation during telogen to anagen transition is mainly controlled by two reciprocal out of phases mechanisms. These include Wnt/β-catenin signaling pathway, which shows crucially roles in hair regeneration. The other one is Bmp signaling pathway, which is decreased in competent telogen phase compared to the refractory telogen phase, leading to hair regeneration. Melanocyte stem cells share the same niche with hair follicle stem cells. Progress has been made in unveiling regenerative behaviors and differentiation of melanocytes. Melanocyte stem cells are activated coordinately with hair follicle stem cells during hair regeneration. They migrate out from the bulge niche to the hair matrix region, and differentiate into melanocytes which generate melanin to pigment hairs.
There is increasing evidence showing that many morphogenetic pathways play key roles in regulating melanocytes behaviors. Of these, Wnt signaling functions as an important pathway controlling the patterning of melanocytes and influencing the decisions of melanocyte stem cells differentiation to pigment the hairs. Wnt3a induces melanocyte stem cell differentiation in vivo and in vitro. Exogenous Wnt recruits β-catenin and Lef1 to bind the promoter of microphthalmia-associated transcription factor (MITF), which functions as a key gene that governs fates of melanocyte lineage cells. Previous study shows that one of the visible signs of hair follicle aging is hair loss. However, the mechanism of hair graying as the other obvious sign of hair follicle aging remains further investigation. Whether Wnt signaling acts as a positive or negative regulator in hair follicle aging is unclear.
Therefore, in this study, we first compared the hair graying phenotype in young and adult mice. Since the important role of Wnt signaling in aging of other tissues, we examined periodic expression of β-catenin which is the effector of Wnt signaling pathway, in melanocyte lineage cells during hair cycling. We found that β-catenin expression was significantly increased both at 34 month telogen phase skin and 34 month anagen phase skin in aged mice, when compared to young mice. We observed that β-catenin expression is not only increased in the hair follicles of aged mice, but also increased at the dermal microenvironment. To explore the function of Wnt signaling on melanocyte differentiation, we over expressed Wnt10b through adenovirus-mediated expression in vivo or in vitro, through intracutaneous injection of adenovirus into the young adult skin, or by adding them into melanocyte stem cells, respectively. Our results indicate that Wnt signaling promotes differentiation of melanocyte stem cell, exhaustion of which leads to hair graying during aging.