A link between the accumulation of DNA damage and loss of multipotency of human mesenchymal stromal cells

H.A.D.C.R. Alves, Ursula Munoz-Najar, Jan de Wit, Auke J.S. Renard, Jan H.J. Hoeijmakers, John M. Sedivy, Clemens van Blitterswijk, Jan de Boer

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Abstract

Human mesenchymal stromal cells (hMSCs) represent an attractive cell source for clinic applications. Besides being multi-potent, recent clinical trials suggest that they secrete both trophic and immunomodulatory factors, allowing allogenic MSCs to be used in a wider variety of clinical situations. The yield of prospective isolation is however very low, making expansion a required step toward clinical applications. Unfortunately, this leads to a significant decrease in their stemness. To identify the mechanism behind loss of multi-potency, hMSCs were expanded until replicative senescence and the concomitant molecular changes were characterized at regular intervals. We observed that, with time of culture, loss of multi-potency was associated with both the accumulation of DNA damage and the respective activation of the DNA damage response pathway, suggesting a correlation between both phenomena. Indeed, exposing hMSCs to DNA damage agents led to a significant decrease in the differentiation potential. We also showed that hMSCs are susceptible to accumulate DNA damage upon in vitro expansion, and that although hMSCs maintained an effective nucleotide excision repair activity, there was a progressive accumulation of DNA damage. We propose a model in which DNA damage accumulation contributes to the loss of differentiation potential of hMSCs, which might not only compromise their potential for clinical applications but also contribute to the characteristics of tissue ageing
Original languageEnglish
Pages (from-to)2729-2738
JournalJournal of cellular and molecular medicine
Volume14
Issue number12
DOIs
Publication statusPublished - 2010

Keywords

  • Human mesenchymal stem cells
  • DNA damage
  • Ageing
  • IR-80846
  • METIS-273574
  • clinical application
  • senescence
  • in vitro expansion

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