Generation of Multipotent Induced Neural Crest by Direct Reprogramming of Human Postnatal Fibroblasts with a Single Transcription Factor
Generation of Multipotent Induced Neural Crest by Direct Reprogramming of Human Postnatal Fibroblasts with a Single Transcription Factor
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DOI：
10.1016/j.stem.2014.07.013
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发表时间：
2014-10-02
期刊：
影响因子：
23.9
通讯作者：
Lee, Gabsang
中科院分区：
文献类型：
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作者：
Kim, Yong Jun;Lim, Hotae;Lee, Gabsang
神经脊细胞(NC)产生多种谱系，包括外周神经元、神经胶质细胞、黑素细胞和间充质衍生物。分离多潜能的人类NC已被证明具有挑战性，限制了我们理解NC发展和模拟NC相关疾病的能力。在这里，我们报告了通过过量表达单个转录因子Sox10结合包括WNT激活在内的环境信号将人成纤维细胞直接重编程为诱导的神经脊(INC)细胞。InC细胞在体内具有广泛的迁移能力，单个InC克隆可以分化为四种主要的NC谱系。我们进一步确定了一种用于预期分离INCS的细胞表面标记，该标记用于从家族性自主神经障碍(FD)患者成纤维细胞中分离和纯化INCS。FD-INC细胞在细胞迁移和选择性mRNA剪接方面存在缺陷，为FD的发病机制提供了新的见解。因此，本研究通过快速高效地对人生后成纤维细胞进行重编程，为研究NC生物学和疾病提供了一个可访问的平台。
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 fourmain 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.