Sun Chong-Kui, Zhou Di, Zhang Zhen, He Liming, Zhang Fan, Wang Xiaowei, Yuan Jie, Chen Qianming, Wu Ling-Gang, Yang Qin
Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.
Nat Commun. 2014 Jun 17;5:4112. doi: 10.1038/ncomms5112.
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 p16(Ink4a) and p19(Arf) 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.
最近的报告显示，通过强制表达转录因子可将成纤维细胞转化为神经元。然而，这种转化背后的机制仍不清楚。在此，我们表明，体外培养老化的胚胎人成纤维细胞向神经元转化的效率低于早期培养阶段细胞的转化效率。此外，参与细胞衰老激活的p16(Ink4a)和p19(Arf)缺失足以将人成纤维细胞和上皮细胞转化为神经元。诱导产生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，诱导产生的神经元具有与成纤维细胞不同的图谱，与通过既定方法诱导的对照神经元的图谱相似。我们进一步注意到，p53的表达会阻断神经元转化，而人端粒酶逆转录酶(hTERT)的表达则会诱导这种转化。我们的结果表明，克服衰老对于体细胞向神经元的转化是关键步骤。
