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Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons

Author

Listed:
  • Houbo Jiang

    (Veterans Affairs Western New York Healthcare System
    State University of New York at Buffalo)

  • Zhimin Xu

    (State University of New York at Buffalo
    Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Ping Zhong

    (Veterans Affairs Western New York Healthcare System
    State University of New York at Buffalo)

  • Yong Ren

    (State University of New York at Buffalo)

  • Gaoyang Liang

    (Howard Hughes Medical Institute, Harvard Medical School)

  • Haley A. Schilling

    (State University of New York at Buffalo)

  • Zihua Hu

    (Center for Computational Research, New York State Center of Excellence in Bioinformatics & Life Sciences, State University of New York at Buffalo)

  • Yi Zhang

    (Howard Hughes Medical Institute, Harvard Medical School)

  • Xiaomin Wang

    (Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing Institute for Brain Disorders, Capital Medical University)

  • Shengdi Chen

    (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Zhen Yan

    (Veterans Affairs Western New York Healthcare System
    State University of New York at Buffalo)

  • Jian Feng

    (Veterans Affairs Western New York Healthcare System
    State University of New York at Buffalo
    Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing Institute for Brain Disorders, Capital Medical University)

Abstract

The direct conversion of fibroblasts to induced dopaminergic (iDA) neurons and other cell types demonstrates the plasticity of cell fate. The low efficiency of these relatively fast conversions suggests that kinetic barriers exist to safeguard cell-type identity. Here we show that suppression of p53, in conjunction with cell cycle arrest at G1 and appropriate extracellular environment, markedly increase the efficiency in the transdifferentiation of human fibroblasts to iDA neurons by Ascl1, Nurr1, Lmx1a and miR124. The conversion is dependent on Tet1, as G1 arrest, p53 knockdown or expression of the reprogramming factors induces Tet1 synergistically. Tet1 knockdown abolishes the transdifferentiation while its overexpression enhances the conversion. The iDA neurons express markers for midbrain DA neurons and have active dopaminergic transmission. Our results suggest that overcoming these kinetic barriers may enable highly efficient epigenetic reprogramming in general and will generate patient-specific midbrain DA neurons for Parkinson’s disease research and therapy.

Suggested Citation

  • Houbo Jiang & Zhimin Xu & Ping Zhong & Yong Ren & Gaoyang Liang & Haley A. Schilling & Zihua Hu & Yi Zhang & Xiaomin Wang & Shengdi Chen & Zhen Yan & Jian Feng, 2015. "Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10100
    DOI: 10.1038/ncomms10100
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