Journal
CELL STEM CELL
Volume 15, Issue 4, Pages 471-487Publisher
CELL PRESS
DOI: 10.1016/j.stem.2014.07.002
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Funding
- Simons Foundation (SFLIFE) [286977]
- NIH [RO1-CA084198]
- Sir Henry Wellcome Postdoctoral Fellowship [098889/Z/12/Z]
- Boehringer Ingelheim Fonds Ph.D. Fellowship
- Jerome and Florence Brill Graduate Student Fellowship
- National Science Foundation Graduate Research Fellowship
- Human Frontier Science Program Postdoctoral Fellowship
- Wellcome Trust [098889/Z/12/Z] Funding Source: Wellcome Trust
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Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question of whether an earlier, naive state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate human pluripotent cells in which transcription factors associated with the ground state of pluripotency are highly upregulated and bivalent chromatin domains are depleted. Comparison with previously reported naive human ESCs indicates that our conditions capture a distinct pluripotent state in humans that closely resembles that of mouse ESCs. This study presents a framework for defining the culture requirements of naive human pluripotent cells.
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