Generation of Multipotent Induced Neural Crest by Direct Reprogramming of Human Postnatal Fibroblasts with a Single Transcription Factor

• Published in: Cell stem cell 2014-10, Vol.15 (4), p.497-506
• Main Authors: Kim, Yong Jun, Lim, Hotae, Li, Zhe, Oh, Yohan, Kovlyagina, Irina, Choi, In Young, Dong, Xinzhong, Lee, Gabsang
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cellular Reprogramming; Chick Embryo; Fibroblasts; Gene Expression Profiling; Genes, Reporter; Green Fluorescent Proteins - metabolism; Humans; Infant; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Neural Crest - cytology; Neural Crest - metabolism; SOXE Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2014.07.013

Neural crest (NC) generates diverse lineages including peripheral neurons, glia, melanocytes, and mesenchymal derivatives. Isolating multipotent human NC has proven challenging, limiting our ability to understand NC development and model NC-associated disorders. Here, we report direct reprogramming of human fibroblasts into induced neural crest (iNC) cells by overexpression of a single transcription factor, SOX10, in combination with environmental cues including WNT activation. iNC cells possess extensive capacity for migration in vivo, and single iNC clones can differentiate into the four main NC lineages. We further identified a cell surface marker for prospective isolation of iNCs, which was used to generate and purify iNCs from familial dysautonomia (FD) patient fibroblasts. FD-iNC cells displayed defects in cellular migration and alternative mRNA splicing, providing insights into FD pathogenesis. Thus, this study provides an accessible platform for studying NC biology and disease through rapid and efficient reprogramming of human postnatal fibroblasts. [Display omitted] •Postnatal human fibroblasts can be reprogrammed into induced neural crest (iNC)•iNC can be generated by overexpression of SOX10 in combination with WNT activation•iNC cells exhibit capacity for multilineage differentiation and migration in vivo•Patient-derived iNC cells allow cellular modeling of neural crest diseases Overexpression of SOX10, in combination with appropriate extracellular cues, is sufficient to directly reprogram human fibroblasts into induced neural crest cells, which can generate the four main neural crest lineages.