2. Academic Validation
  3. Notch inhibition allows oncogene-independent generation of iPS cells

Notch inhibition allows oncogene-independent generation of iPS cells

  • Nat Chem Biol. 2014 Aug;10(8):632-639. doi: 10.1038/nchembio.1552.
Justin K Ichida # 1 2 3,  Julia Tcw # 1 2 4,  Luis A Williams 1 2,  Ava C Carter 1 2,  Yingxiao Shi 3,  Marcelo T Moura 1 2,  Michael Ziller 1 5,  Sean Singh 1 2,  Giovanni Amabile 6,  Christoph Bock 1 5,  Akihiro Umezawa 7,  Lee L Rubin 1,  James E Bradner 8 9,  Hidenori Akutsu 7,  Alexander Meissner 1 5,  Kevin Eggan 1 2 4
Affiliations

Affiliations

  • 1 Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 2 Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.
  • 3 Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
  • 4 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
  • 5 Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
  • 6 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
  • 7 Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, USA.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
  • 9 Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
  • # Contributed equally.
PMID: 24952596 DOI: 10.1038/nchembio.1552
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.

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