title: Senescence impairs direct conversion of human somatic cells to neurons.
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 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.
authors.affiliation: Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.|State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.
authors.forename: Chong-Kui
authors.initials: CK
authors.lastname: Sun
authors.affiliation: Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Zhou
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: He
authors.affiliation: Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Medical College, Jinan University, Guangzhou 510632, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA.
authors.forename: Ling-Gang
authors.initials: LG
authors.lastname: Wu
authors.affiliation: Cancer Biology Division, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase