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Nat Chem Biol DOI:10.1038/nchembio.1552

Notch inhibition allows oncogene-independent generation of iPS cells.

Publication TypeJournal Article
Year of Publication2014
AuthorsIchida, JK, TCW, J, W, JTC, Williams, LA, Carter, AC, Shi, Y, Moura, MT, Ziller, M, Singh, S, Amabile, G, Bock, C, Umezawa, A, Rubin, LL, Bradner, JE, Akutsu, H, Meissner, A, Eggan, K
JournalNat Chem Biol
Volume10
Issue8
Pages632-9
Date Published2014 Aug
ISSN1552-4469
KeywordsAnimals, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Dipeptides, DNA-Binding Proteins, Genes, myc, Genes, p53, Humans, Keratinocytes, Kruppel-Like Transcription Factors, Methyltransferases, Mice, Oncogenes, Pluripotent Stem Cells, Receptors, Notch, Signal Transduction, Transcription Factors
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.

URLhttp://dx.doi.org/10.1038/nchembio.1552
DOI10.1038/nchembio.1552
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24952596?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID24952596
PubMed Central IDPMC4310751
Grant List1K99NS077435-01A1 / NS / NINDS NIH HHS / United States
R01 GM096067 / GM / NIGMS NIH HHS / United States
P01 GM099117 / GM / NIGMS NIH HHS / United States
5R01GM096067 / GM / NIGMS NIH HHS / United States
5P01GM099117 / GM / NIGMS NIH HHS / United States
K99 NS077435 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R00 NS077435 / NS / NINDS NIH HHS / United States
4R00NS077435-03 / NS / NINDS NIH HHS / United States