The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.
Cell Rep. 2013 Apr 25;3(4):1140-52. doi: 10.1016/j.celrep.2013.03.025. Epub 2013 Apr 11.
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.
黑素细胞是神经嵴（NC）起源的色素产生细胞，负责保护皮肤免受 UV 照射。多能干细胞（PSC）技术为研究人类黑素细胞发育和疾病提供了一种很有前途的方法。在这里，我们报告说，在双重 SMAD 抑制条件下，适时暴露于 WNT、BMP 和 EDN3 信号的激活剂可依次诱导 NC 和黑素细胞前体命运。使用 SOX10::GFP 人胚胎干细胞（hESC）报告系，我们证明 WNT 激活的时间起始对于人类 NC 诱导特别关键。随后，hESC 衍生的黑素细胞成熟产生与成年黑素细胞的分子和功能特性相匹配的纯群体。来自 Hermansky-Pudlak 综合征和 Chediak-Higashi 综合征患者特异性诱导 PSC（iPSC）的黑素细胞忠实地再现了与疾病相关的色素沉着缺陷的超微结构特征。我们的数据定义了 NC 诱导过程中对 WNT 信号的高度特异性要求，并能够产生纯群体的人 iPSC 衍生的黑素细胞，用于忠实建模色素沉着障碍。
