Systematic identification of culture conditions for induction and maintenance of naive human pluripotency

Thorold W. Theunissen, Benjamin E. Powell, Haoyi Wang, Maya Mitalipova, Dina A. Faddah, Jessica Reddy, Zi Peng Fan, Dorothea Maetzel, Kibibi Ganz, Linyu Shi, Tenzin Lungjangwa, Sumeth Imsoonthornruksa, Yonatan Stelzer, Sudharshan Rangarajan, Ana D'Alessio, Jianming Zhang, Qing Gao, Meelad M. Dawlaty, Richard A. Young, Nathanael S. GrayRudolf Jaenisch

Research output: Contribution to journalArticle

404 Scopus citations

Abstract

Embryonic stem cells (ESCs) of mice and humans have distinctmolecular and biological characteristics, raising thequestionofwhetheranearlier, "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, amolecular 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 associatedwith 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 ofmouse ESCs. This study presents a framework for defining the culture requirements of naive human pluripotent cells.

Original languageEnglish (US)
Pages (from-to)471-487
Number of pages17
JournalCell Stem Cell
Volume15
Issue number4
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Theunissen, T. W., Powell, B. E., Wang, H., Mitalipova, M., Faddah, D. A., Reddy, J., Fan, Z. P., Maetzel, D., Ganz, K., Shi, L., Lungjangwa, T., Imsoonthornruksa, S., Stelzer, Y., Rangarajan, S., D'Alessio, A., Zhang, J., Gao, Q., Dawlaty, M. M., Young, R. A., ... Jaenisch, R. (2014). Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell, 15(4), 471-487. https://doi.org/10.1016/j.stem.2014.07.002