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Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells

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  • Uri Ben-David

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
    Cancer Program, Broad Institute of Harvard and MIT)

  • Gal Arad

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University)

  • Uri Weissbein

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University)

  • Berhan Mandefro

    (Cedars-Sinai Medical Center)

  • Adva Maimon

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University)

  • Tamar Golan-Lev

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University)

  • Kavita Narwani

    (Cedars-Sinai Medical Center)

  • Amander T. Clark

    (Cell, and Developmental Biology, University of California-Los Angeles
    Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles)

  • Peter W. Andrews

    (Centre for Stem Cell Biology, University of Sheffield)

  • Nissim Benvenisty

    (Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University)

  • Juan Carlos Biancotti

    (Cedars-Sinai Medical Center
    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California)

Abstract

Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is trisomy of chromosome 12. Here we dissect the cellular and molecular implications of this trisomy in hPSCs. Global gene expression analyses reveal that trisomy 12 profoundly affects the gene expression profile of hPSCs, inducing a transcriptional programme similar to that of germ cell tumours. Comparison of proliferation, differentiation and apoptosis between diploid and aneuploid hPSCs shows that trisomy 12 significantly increases the proliferation rate of hPSCs, mainly as a consequence of increased replication. Furthermore, trisomy 12 increases the tumorigenicity of hPSCs in vivo, inducing transcriptionally distinct teratomas from which pluripotent cells can be recovered. Last, a chemical screen of 89 anticancer drugs discovers that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors. Together, these findings demonstrate the extensive effect of trisomy 12 and highlight its perils for successful hPSC applications.

Suggested Citation

  • Uri Ben-David & Gal Arad & Uri Weissbein & Berhan Mandefro & Adva Maimon & Tamar Golan-Lev & Kavita Narwani & Amander T. Clark & Peter W. Andrews & Nissim Benvenisty & Juan Carlos Biancotti, 2014. "Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5825
    DOI: 10.1038/ncomms5825
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    Cited by:

    1. Rong Xiao & Deshu Xu & Meili Zhang & Zhanghua Chen & Li Cheng & Songjie Du & Mingfei Lu & Tonghai Zhou & Ruoyan Li & Fan Bai & Yue Huang, 2024. "Aneuploid embryonic stem cells drive teratoma metastasis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Maria Arez & Melanie Eckersley-Maslin & Tajda Klobučar & João Gilsa Lopes & Felix Krueger & Annalisa Mupo & Ana Cláudia Raposo & David Oxley & Samantha Mancino & Anne-Valerie Gendrel & Bruno Bernardes, 2022. "Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Uri Weissbein & Omer Plotnik & Dan Vershkov & Nissim Benvenisty, 2017. "Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells," PLOS Genetics, Public Library of Science, vol. 13(8), pages 1-16, August.

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