UV-Induced Wnt7a in the Human Skin Microenvironment Specifies the Fate of Neural Crest–Like Cells via Suppression of Notch

Abstract

Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here, we show that in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced proliferation of NCSC-like cells, induced cell death, and down-regulated non-canonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is up-regulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a crosstalk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.

Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients

“…The WNT pathway is involved in melanocyte differentiation (Yamada et al, 2013;Fukunaga-Kalabis et al, 2015), and we have demonstrated that this pathway is altered in vitiligo skin. In order to induce the differentiation of melanocyte stem cells, we pharmacologically activated the WNT pathway in ex vivo vitiligo skin using the WNT agonist (SKL2001) and the glycogen synthase kinase (GSK)3β inhibitors lithium chloride (LiCl) and CHIR99021.…”

Narrowband UVB treatment induces expression of WNT7B, WNT10B and TCF7L2 in psoriasis skin

“…The aim of this study was to describe the expression of WNT7B, WNT10B, WNT16 and TCF7L2 in lesional and non-lesional skin and in whole blood of patients with psoriasis compared to healthy individuals and to investigate if SNPs in these genes can be correlated to psoriasis. Previous studies show that ultraviolet (UV) radiation upregulates members of the WNT/β-catenin pathway [16, 50]. To investigate the effect of UV radiation on WNT7B, WNT10B, WNT16 and TCF7L2, gene expression levels were analyzed before and after narrowband UVB (nbUVB) treatment.…”

LEF-1 Regulates Tyrosinase Gene Transcription In Vitro

“…Melanocytes and their progenitor cells melanoblasts originate from multi-potential neural crest stem cells, which then migrate through the developing embryo and localize to specific sites in the body. In addition, they comprise a stem cell pool for their regeneration [ 1 , 2 ], which may be an important factor in melanoma development from melanocytes [ 3 ]. The visible pigmentation in skin, hair and eyes primarily depends on the presence of melanin, a macromolecule synthesized by melanocytes.…”