Differentiation-Related Response to DNA Breaks in Human Mesenchymal Stem Cells§

Authors

  • Lisa Oliver,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
    3. Centre Hospitalier-Universitaire (CHU) de Nantes, Nantes, France
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  • Erika Hue,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
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  • Quentin Séry,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
    3. Institut de Cancérologie de l'Ouest—René Gauducheau, St. Herblain, Nantes, France
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  • Audrey Lafargue,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
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  • Claire Pecqueur,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
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  • François Paris,

    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
    3. Institut de Cancérologie de l'Ouest—René Gauducheau, St. Herblain, Nantes, France
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  • François M. Vallette

    Corresponding author
    1. CRCNA—INSERM UMR 892—CNRS UMR 6299, Nantes, France
    2. Faculté de Médecine, Université de Nantes, Nantes, France
    3. Institut de Cancérologie de l'Ouest—René Gauducheau, St. Herblain, Nantes, France
    • Centre de Recherche en Cancérologie Nantes Angers, INSERM UMR 892 CNRS UMR 6299 Université de Nantes. 8, Quai Moncousu BP 70721, 44007 Cedex 1, Nantes, France
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    • Telephone: 33-228080324; Fax: 33-228080329


  • Author contributions: L.O.: conception and design, collection and assembly of data, and data analysis and interpretation and writing; E.H., Q.S., A.L., and C.P.: collection and assembly of data; F.P.: data analysis and interpretation; F.V.: conception and design and data analysis and interpretation and writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS January 22, 2013.

Abstract

We have recently shown that the in vitro differentiation of human mesenchymal stem cells (hMSCs) was accompanied by an increased sensitivity toward apoptosis; however, the mechanism responsible for this shift is not known. Here, we show that the repair of DNA double-strand breaks (DSBs) was more rapid in undifferentiated hMSCs than in differentiated osteoblasts by quantification of the disappearance of γ-H2AX foci in the nuclei after γ-irradiation-induced DNA damage. In addition, there was a marked and prolonged increase in the level of nuclear Ku70 and an increased phosphorylation of DNA-PKcs. This was accompanied by an augmentation in the phosphorylation of ATM in hMSCs post-irradiation suggesting the nonhomologous end joining repair mechanism. However, when hMSCs were induced to differentiate along the osteogenic or adipogenic pathways; irradiation of these cells caused an expeditious and robust cell death, which was primarily apoptotic. This was in sharp contrast to undifferentiated hMSCs, which were highly resistant to irradiation and/or temozolomide-induced DSBs. In addition, we observed a 95% recovery from DSB in these cells. Our results suggest that apoptosis and DNA repair are major safeguard mechanisms in the control of hMSCs differentiation after DNA damage. STEM CELLS 2013;31:800–807

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