Nature 462, 595-601 (3 December 2009) | doi:10.1038/nature08592; Received 18 June 2009; Accepted 21 October 2009; Published online 8 November 2009

Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna1,4, Krishanu Saha1,4, Bernardo Pando2, Jeroen van Zon2,3, Christopher J. Lengner1, Menno P. Creyghton1, Alexander van Oudenaarden2,3 & Rudolf Jaenisch1,3

  1. The Whitehead Institute for Biomedical Research,
  2. Department of Physics,
  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
  4. These authors contributed equally to this work.

Correspondence to: Jacob Hanna1,4Rudolf Jaenisch1,3 Correspondence and requests for materials should be addressed to R.J. (Email: or J.H. (Email:


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.


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