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Senescence impairs direct conversion of human somatic cells to neurons

Nature Communications volume 5, Article number: 4112 (2014) | Download Citation

Abstract

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.

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Acknowledgements

We thank Andrew Yoo for helpful suggestions and reagents, Buck Rogers and Wilbur Song for proofreading this manuscript. This work is supported in part by grants from the Natural Science Foundation (No. 81228017), Natural Science Foundation of Hunan Province (No.10JJ5043), the Concern Foundation (Q.Y.) and NIH CA129440 (Q.Y.).

Author information

Author notes

    • Chong-kui Sun
    • , Di Zhou
    •  & Zhen Zhang

    The first three authors contributed equally to this work

Affiliations

  1. Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA

    • Chong-kui Sun
    • , Di Zhou
    • , Fan Zhang
    • , Xiaowei Wang
    •  & Qin Yang
  2. State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China

    • Chong-kui Sun
    •  & Qianming Chen
  3. National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA

    • Zhen Zhang
    • , Liming He
    •  & Ling-Gang Wu
  4. Medical College, Jinan University, Guangzhou 510632, China

    • Jie Yuan

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Contributions

Q.Y. generated the hypotheses, designed experiments and analysed the data. D.Z., C.-k.S., Z.Z., L.H., F.Z., J.Y. and Q.C. performed experiments and generated the data. L.-g.W. and X.W. designed experiments and analysed the data. Q.Y., D.Z., Z.Z. and L.-g.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ling-Gang Wu or Qin Yang.

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DOI

https://doi.org/10.1038/ncomms5112

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