title: Modeling neural crest induction, melanocyte specification, and disease-related pigmentation defects in hESCs and patient-specific iPSCs.
abstract: Melanocytes are pigment-producing cells of neural crest (NC) origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC) technology offers a promising approach for studying human melanocyte development and disease. Here, we report that timed exposure to activators of WNT, BMP, and EDN3 signaling triggers the sequential induction of NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC) reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs) faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders.
authors.affiliation: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Mica
authors.forename: Gabsang
authors.initials: G
authors.lastname: Lee
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Chambers
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Tomishima
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002609:Chediak-Higashi Syndrome / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism; D010858:Pigmentation; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D019334:Endothelin-3; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D051153:Wnt Proteins; D049452:Green Fluorescent Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3