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Nat Chem Biol. 2014 Aug;10(8):632-9. doi: 10.1038/nchembio.1552. Epub 2014 Jun 22.

Notch inhibition allows oncogene-independent generation of iPS cells.

Author information

  • 11] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA. [3] Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California, USA. [4].
  • 21] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA. [3] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. [4].
  • 31] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA.
  • 4Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California, USA.
  • 51] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 6Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 7Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 8Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
  • 91] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • 101] Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Howard Hughes Medical Institute, Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA. [3] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

Abstract

The reprogramming of somatic cells to pluripotency using defined transcription factors holds great promise for biomedicine. However, human reprogramming remains inefficient and relies either on the use of the potentially dangerous oncogenes KLF4 and CMYC or the genetic inhibition of the tumor suppressor gene p53. We hypothesized that inhibition of signal transduction pathways that promote differentiation of the target somatic cells during development might relieve the requirement for non-core pluripotency factors during induced pluripotent stem cell (iPSC) reprogramming. Here, we show that inhibition of Notch greatly improves the efficiency of iPSC generation from mouse and human keratinocytes by suppressing p21 in a p53-independent manner and thereby enriching for undifferentiated cells capable of long-term self-renewal. Pharmacological inhibition of Notch enabled routine production of human iPSCs without KLF4 and CMYC while leaving p53 activity intact. Thus, restricting the development of somatic cells by altering intercellular communication enables the production of safer human iPSCs.

PMID:
24952596
[PubMed - indexed for MEDLINE]
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