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Direct cell reprogramming is a stochastic process amenable to acceleration

Author

Listed:
  • Jacob Hanna

    (The Whitehead Institute for Biomedical Research,)

  • Krishanu Saha

    (The Whitehead Institute for Biomedical Research,)

  • Bernardo Pando

    (Department of Physics,)

  • Jeroen van Zon

    (Department of Physics,
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

  • Christopher J. Lengner

    (The Whitehead Institute for Biomedical Research,)

  • Menno P. Creyghton

    (The Whitehead Institute for Biomedical Research,)

  • Alexander van Oudenaarden

    (Department of Physics,
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

  • Rudolf Jaenisch

    (The Whitehead Institute for Biomedical Research,
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

Abstract

Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

Suggested Citation

  • Jacob Hanna & Krishanu Saha & Bernardo Pando & Jeroen van Zon & Christopher J. Lengner & Menno P. Creyghton & Alexander van Oudenaarden & Rudolf Jaenisch, 2009. "Direct cell reprogramming is a stochastic process amenable to acceleration," Nature, Nature, vol. 462(7273), pages 595-601, December.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7273:d:10.1038_nature08592
    DOI: 10.1038/nature08592
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    Cited by:

    1. Francesco Panariello & Onelia Gagliano & Camilla Luni & Antonio Grimaldi & Silvia Angiolillo & Wei Qin & Anna Manfredi & Patrizia Annunziata & Shaked Slovin & Lorenzo Vaccaro & Sara Riccardo & Valenti, 2023. "Cellular population dynamics shape the route to human pluripotency," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Nikolaos K. Voulgarakis, 2024. "Hierarchical Symmetry-Breaking Model for Stem Cell Differentiation," Mathematics, MDPI, vol. 12(9), pages 1-15, May.
    3. Miles Miller & Marc Hafner & Eduardo Sontag & Noah Davidsohn & Sairam Subramanian & Priscilla E M Purnick & Douglas Lauffenburger & Ron Weiss, 2012. "Modular Design of Artificial Tissue Homeostasis: Robust Control through Synthetic Cellular Heterogeneity," PLOS Computational Biology, Public Library of Science, vol. 8(7), pages 1-18, July.

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