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. Gray; Rudolf Jaenisch

doi:10.1016/j.stem.2014.07.002

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 journal › Article › peer-review

608 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 language	English (US)
Pages (from-to)	471-487
Number of pages	17
Journal	Cell Stem Cell
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2014.07.002
State	Published - 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2014.07.002

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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

Theunissen, TW, Powell, BE, Wang, H, Mitalipova, M, Faddah, DA, Reddy, J, Fan, ZP, Maetzel, D, Ganz, K, Shi, L, Lungjangwa, T, Imsoonthornruksa, S, Stelzer, Y, Rangarajan, S, D'Alessio, A, Zhang, J, Gao, Q, Dawlaty, MM, Young, RA, Gray, NS & Jaenisch, R 2014, 'Systematic identification of culture conditions for induction and maintenance of naive human pluripotency', Cell Stem Cell, vol. 15, no. 4, pp. 471-487. https://doi.org/10.1016/j.stem.2014.07.002

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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.",

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

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doi = "10.1016/j.stem.2014.07.002",

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AU - Powell, Benjamin E.

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AU - Faddah, Dina A.

AU - Reddy, Jessica

AU - Fan, Zi Peng

AU - Maetzel, Dorothea

AU - Ganz, Kibibi

AU - Shi, Linyu

AU - Lungjangwa, Tenzin

AU - Imsoonthornruksa, Sumeth

AU - Stelzer, Yonatan

AU - Rangarajan, Sudharshan

AU - D'Alessio, Ana

AU - Zhang, Jianming

AU - Gao, Qing

AU - Dawlaty, Meelad M.

AU - Young, Richard A.

AU - Gray, Nathanael S.

AU - Jaenisch, Rudolf

PY - 2014

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

Abstract

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