Senescence impairs successful reprogramming to pluripotent stem cells

  1. Ana Banito1,
  2. Sheikh T. Rashid2,
  3. Juan Carlos Acosta1,
  4. SiDe Li3,4,
  5. Carlos F. Pereira5,
  6. Imbisaat Geti2,
  7. Sandra Pinho6,
  8. Jose C. Silva7,
  9. Veronique Azuara6,
  10. Martin Walsh3,4,
  11. Ludovic Vallier2 and
  12. Jesús Gil1,8
  1. 1Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom;
  2. 2Laboratory for Regenerative Medicine, University of Cambridge, Department of Surgery, Cambridge CB2 0SZ, United Kingdom;
  3. 3Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA;
  4. 4Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA;
  5. 5Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom;
  6. 6Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom;
  7. 7Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, United Kingdom

    Abstract

    Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier. Expression of the four reprogramming factors triggers senescence by up-regulating p53, p16INK4a, and p21CIP1. Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells.

    Keywords

    Footnotes

    | Table of Contents

    This Article

    1. Published in Advance August 20, 2009, doi: 10.1101/gad.1811609 Genes & Dev. 23: 2134-2139 Copyright © 2009 by Cold Spring Harbor Laboratory Press

    Article Category

    Share

    Current Issue

    1. March 1, 2024, 38 (5-6)
    1. Current Issue
    1. Alert me to new issues of G&D

    Life Science Alliance