Conversion of fibroblasts to neural cells by p53 depletion.
Conversion of fibroblasts to neural cells by p53 depletion.
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通过p53耗竭将成纤维细胞转化为神经细胞。
DOI：
10.1016/j.celrep.2014.11.040
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发表时间：
2014-12-24
期刊：
影响因子：
8.8
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
Zhou D;Zhang Z;He LM;Du J;Zhang F;Sun CK;Zhou Y;Wang XW;Lin G;Song KM;Wu LG;Yang Q
最近成功地诱导了从成纤维细胞到神经元的转化。然而，对潜在的机制知之甚少。在这里，我们发现，p53的耗竭单独转化成纤维细胞到所有三个主要的神经谱系。诱导的神经元细胞表达多种神经元特异性蛋白，并产生动作电位和递质受体介导的电流。令人惊讶的是，耗尽不影响众所周知的致瘤性p53靶点p21。相反，p53的敲低上调神经源性转录因子，这反过来又促进成纤维细胞-神经元转化。p53结合神经源性转录因子Neurod 2的启动子并调节其在成纤维细胞-神经元转化过程中的表达。此外，我们的方法在晚期传代成纤维细胞中提供了高转化效率。全基因组转录分析表明，p53缺陷诱导的神经元表现出的表达谱不同的亲本成纤维细胞和类似的控制诱导的神经元。这些结果可能有助于理解和改善神经转换机制，以开发强大的神经元替代治疗策略。
Conversion from fibroblasts to neurons has recently been successfully induced. However, the underlying mechanisms are poorly understood. Here, we find that depletion of p53 alone converts fibroblasts into all three major neural lineages. The induced neuronal cells express multiple neuron-specific proteins and generate action potentials and transmitter-receptor-mediated currents. Surprisingly, depletion does not affect the well-known tumorigenic p53 target, p21. Instead, knockdown of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblast-neuron conversion. Furthermore, our method provides a high efficiency of conversion in late-passage fibroblasts. Genome-wide transcriptional analysis shows that the p53-deficiency-induced neurons exhibit an expression profile different from parental fibroblasts and similar to control-induced neurons. The results may help to understand and improve neural conversion mechanisms to develop robust neuron-replacement therapy strategies.