Senescence impairs direct conversion of human somatic cells to neurons.
Senescence impairs direct conversion of human somatic cells to neurons.
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DOI：
10.1038/ncomms5112
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发表时间：
2014-06-17
影响因子：
16.6
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
Sun CK;Zhou D;Zhang Z;He L;Zhang F;Wang X;Yuan J;Chen Q;Wu LG;Yang Q
最近的报道表明，成纤维细胞可以通过转录因子的强制表达而转化为神经元。然而，这种转换背后的机制仍然不清楚。在这里，我们发现在培养中老化的胚胎人成纤维细胞的神经元转化效率低于早期培养阶段的细胞。此外，参与细胞衰老激活的p16INK4a和p19Arf的缺失足以将人成纤维细胞和上皮细胞转化为神经元。诱导的神经元表达神经元特异性蛋白，产生动作电位和神经递质受体介导的电流。全基因组转录分析表明，诱导的神经元具有不同于成纤维细胞的特征，而与现有方法诱导的对照神经元相似。我们进一步注意到，p53的表达阻止了神经元的转化，而人端粒酶逆转录酶(HTERT)的表达则诱导了神经元的转化。我们的结果表明，克服衰老是体细胞神经细胞转化的关键步骤。
Recent reports have shown that fibroblasts can be converted to neurons by forced expression of transcription factors. However, the mechanisms underlying this conversion remain unclear. Here, we show that the efficiency of neuronal conversion of embryonic human fibroblasts aged in culture is lower than that in cells in early culture stages. Moreover, depletion of p16Ink4a and p19Arf involved in the activation of cellular senescence is sufficient to convert human fibroblast and epithelial cells into neurons. The induced neurons express neuron-specific proteins, generate action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis shows that the induced neurons have a profile different from fibroblasts and similar to that of control neurons induced by established methods. We further noted that expression of p53 blocks the neuronal conversion, whereas expression of human telomerase reverse transcriptase (hTERT) induces it. Our results indicate that overcoming senescence is a crucial step for neuronal conversion of somatic cells.