A research team at NYU Langone Medical Center has uncovered a pair of molecular signals that control the hair and skin color in mice and humans. Manipulation of these very signals may lead to therapies or even drugs to treat skin pigment disorders, such as vitiligo.
Vitiligo is somewhat disfiguring condition characterized by the loss of skin pigmentation, leaving a blotchy, white appearance. Finding ways to activate these two signaling pathways may provide clinicians with the means to mobilize the pigment-synthesizing stem cells that place pigment in skin structures and, potentially, repigment the pigment-bearing structures that were damaged in cases of vitiligo. Such treatment might also repigment grayed hair cells in older people, and even correct the discoloration that affects scars.
Workers in the laboratory of Mayumi Ito at the Ronald O. Perelman Department of Dermatology and the Department of Cell Biology showed that a skin-based stem cell population of pigment-producing cells, known as “melanocytes,” grow and regenerate in response to two molecular signals. The Endothelin receptor type B (EdnrB) protein is found on the surfaces of melanocytes. EdnrB signaling promotes the growth and differentiation of melanocyte stem cells (McSCs). Activation of EdnrB greatly enhances the regeneration of hair-based and epidermal-based melanocytes. However, EdnrB does act alone. Instead, the effect of EdnrB depends upon active Wnt signaling. This Wnt signal is initiated by the secretion of Wnt glycoproteins by the hair follicle cells.
This work was published in Cell Reports, April 2016 DOI: http://dx.doi.org/10.1016/j.celrep.2016.04.006.
Previous work on EdnrB has established that it plays a central role in blood vessel development. This work by Ito and his team is the first indication that pigment-producing melanocytes, which provide color to hair and skin, are controlled by this protein.
A lack of EdnrB signaling in mice caused premature graying of the hair. However, stimulating the EdnrB pathway resulted in a 15-fold increase in melanocyte stem cell pigment production, and by two months, the mice showed hyperpigmentation. In fact, wounded skin in these mice became pigmented upon healing.
If the Wnt signaling pathway was blocked, stem cell growth and maturation sputtered and stalled and never got going, even when the EdnrB pathway was working properly. These mice had unpigmented fur (see E in figure below).
However, perhaps the most exciting finding for Ito and his colleagues was that Wnt-dependent, EdnrB signaling rescued the defects in melanocyte regeneration caused by loss of the Mc1R receptor. This is precisely the receptor that does not function properly in red-heads, which causes them to have red hair and very light skin that burns easily in the sun. These data suggest that Edn/EdnrB/Wnt signaling in McSCs can be used therapeutically to promote photoprotective-melanocyte regeneration in those patients with increased risk of skin cancers due to their very lightly colored skin.