EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

Abstract

Delineating the crosstalk between distinct signaling pathways is key to understanding the diverse and dynamic responses of adult stem cells during tissue regeneration. Here we demonstrate that the Edn/EdnrB signaling pathway can interact with other signaling pathways to elicit distinct stem cell functions during tissue regeneration. EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells (McSCs), dramatically enhancing the regeneration of hair and epidermal melanocytes. This effect is dependent upon active Wnt signaling that is initiated by Wnt ligand secretion from the hair follicle epithelial niche. Further, this Wnt-dependent EdnrB signaling can rescue the defects in melanocyte regeneration caused by Mc1R loss. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote photoprotective-melanocyte regeneration, which may be useful for those with increased risk of skin cancers due to Mc1R variants.

Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials

“…These data indicate that MITF may enhance the role of Wnt/β‐catenin signalling in proliferation and differentiation of McSCs in a feedback mechanism. Activation of Wnt signalling or increased Edn1/2 in the hair bulge promotes McSCs proliferation by binding Edn receptor B, which also governs the regenerative response of both mouse and human McSCs during large wound healing . Both Edn1 and Edn2 are important for McSCs activation.…”

“…The regenerated hair follicles during healing of large wound are unpigmented . Nevertheless, the regenerated hair follicle can turn to be pigmented when Endothelin is overexpressed . SCF/c‐kit signalling and melanocortin 1 receptor (Mc1r) guide the McSCs directly migrate from the hair bulge to epidermis and mediate their differentiation for epidermal pigmentation.…”

Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata

“…Bulge stem cells, the source for repigmentation in vitiligo, most likely activated in anagen (Takeo et al, 2016) (Figure 1a), can proliferate, migrate along the infundibulum, and differentiate to repopulate the depigmented epidermis devoid of melanocytes (Goldstein et al, 2015;Guo et al, 2016). A stimulus for this process is narrowband UVB (NB-UVB).…”

Flavonoids with Two OH Groups in the B-Ring Promote Pigmented Hair Regeneration

“…These skin regeneration-associated melanocytes have the potential to differentiate into follicular melanocytes of regenerating hair follicles to form pigmented hairs. 2,3) Wnt signaling, first produced in the follicular keratinocyte stem cells, is known to stimulate both hair follicular keratinocytes and follicular melanocyte stem cells to induce coordinated pigmented hair follicle regeneration after wounding. 3) Furthermore, efficient regeneration of pigmented hairs was observed when mice were wounded at 5 weeks after birth.…”