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  Reduced MEK inhibition preserves genomic stability in naive human embryonic stem cells

Di Stefano, B., Ueda, M., Sabri, S., Brumbaugh, J., Huebner, A. J., Sahakyan, A., et al. (2018). Reduced MEK inhibition preserves genomic stability in naive human embryonic stem cells. Nature methods, 15(9), 732-740. doi:10.1038/s41592-018-0104-1.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-4C93-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-4C94-1
Genre: Journal Article

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 Creators:
Di Stefano, Bruno , Author
Ueda, Mai , Author
Sabri, Shan , Author
Brumbaugh, Justin , Author
Huebner, Aaron J. , Author
Sahakyan, Anna , Author
Clement, Kendell , Author
Clowers, Katie J. , Author
Erickson, Alison R. , Author
Shioda, Keiko , Author
Gygi, Steven P. , Author
Gu, Hongcang , Author
Shioda, Toshi, Author
Meissner, Alexander1, 2, 3, 4, Author              
Takashima, Yasuhiro, Author
Plath, Kathrin , Author
Hochedlinger, Konrad , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA, ou_persistent22              
3Harvard Stem Cell Institute, Cambridge, MA, USA, ou_persistent22              
4Broad Institute of MIT and Harvard, Cambridge, MA, USA, ou_persistent22              

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 Abstract: Human embryonic stem cells (hESCs) can be captured in a primed state in which they resemble the postimplantation epiblast, or in a naive state where they resemble the preimplantation epiblast. Naive-cell-specific culture conditions allow the study of preimplantation development ex vivo but reportedly lead to chromosomal abnormalities, which compromises their utility in research and potential therapeutic applications. Although MEK inhibition is essential for the naive state, here we show that reduced MEK inhibition facilitated the establishment and maintenance of naive hESCs that retained naive-cell-specific features, including global DNA hypomethylation, HERVK expression, and two active X chromosomes. We further show that hESCs cultured under these modified conditions proliferated more rapidly; accrued fewer chromosomal abnormalities; and displayed changes in the phosphorylation levels of MAPK components, regulators of DNA damage/repair, and cell cycle. We thus provide a simple modification to current methods that can enable robust growth and reduced genomic instability in naive hESCs.

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Language(s): eng - English
 Dates: 2018-07-062018-08-202018-09
 Publication Status: Published in print
 Pages: -
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 Identifiers: DOI: 10.1038/s41592-018-0104-1
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Title: Nature methods
  Other : Nature methods
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: 9 Volume / Issue: 15 (9) Sequence Number: - Start / End Page: 732 - 740 Identifier: ISSN: 1548-7091
CoNE: https://pure.mpg.de/cone/journals/resource/111088195279556