title: Notch inhibition allows oncogene-independent generation of iPS cells.
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.
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.|Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors: Justin K
authors: JK
authors: Ichida
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.|Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors: Julia
authors: J
authors: Tcw
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.
authors: Luis A
authors: LA
authors: Williams
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.
authors: Ava C
authors: AC
authors: Carter
authors: Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, 1425 San Pablo Street, Los Angeles, CA 90033, USA.
authors: Yingxiao
authors: Y
authors: Shi
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.
authors: Marcelo T
authors: MT
authors: Moura
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Michael
authors: M
authors: Ziller
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.
authors: Sean
authors: S
authors: Singh
authors: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
authors: Giovanni
authors: G
authors: Amabile
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Christoph
authors: C
authors: Bock
authors: Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, USA.
authors: Akihiro
authors: A
authors: Umezawa
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors: Lee L
authors: LL
authors: Rubin
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.|Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
authors: James E
authors: JE
authors: Bradner
authors: Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, USA.
authors: Hidenori
authors: H
authors: Akutsu
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Alexander
authors: A
authors: Meissner
authors: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute and Stanley Center for Psychiatric Research.|Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors: Kevin
authors: K
authors: Eggan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D016259:Genes, myc; D016158:Genes, p53; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009857:Oncogenes / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D004151:Dipeptides; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C430872:MAML1 protein, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D014157:Transcription Factors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase