title: 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 the proliferation of NCSC-like cells, induced cell death, and downregulated noncanonical 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 upregulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a cross talk 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.
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA. Electronic address: mkalabis@wistar.org.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Denitsa M
authors.initials: DM
authors.lastname: Hristova
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Joshua X
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA; Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany.
authors.forename: Markus V
authors.initials: MV
authors.lastname: Heppt
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gyurdieva
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.affiliation: Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA. Electronic address: herlynm@wistar.org.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010858:Pigmentation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D012879:Skin Physiological Phenomena; D013234:Stem Cells / Q000166:cytology; D014466:Ultraviolet Rays; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; C085389:WNT5A protein, human; C092778:WNT7A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin