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Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification

Nature Clinical Practice Cardiovascular Medicine volume 3, pages S114–S122 (2006)Cite this article

Abstract

Embryonic stem cells (ESCs) can be propagated indefinitely in culture, while retaining the ability to differentiate into any cell type in the organism. The molecular and cellular mechanisms underlying ESC pluripotency are, however, poorly understood. We characterize a population of early mesoderm-specified (EM) progenitors that is generated from mouse ESCs by bone morphogenetic protein stimulation. We further show that pluripotent ESCs are actively regenerated from EM progenitors by the action of the divergent homeodomain-containing protein Nanog, which, in turn, is upregulated in EM progenitors by the combined action of leukemia inhibitory factor and the early mesoderm transcription factor T/Brachyury. These findings uncover specific roles of leukemia inhibitory factor, Nanog, and bone morphogenetic protein in the self-renewal of ESCs and provide novel insights into the cellular bases of ESC pluripotency.

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Figure 1: Leukemia inhibitory factor regulates the percentage of T-expressing cells in mouse embryonic stem cell cultures
Figure 2: Dedifferentiation of lineage-specified mesoderm progenitors into pluripotent stem cells
Figure 3: Nanog is sufficient and necessary for dedifferentiation of early mesoderm-specified progenitors into pluripotent stem cells
Figure 4: Maintenance of embryonic stem cell pluripotency by a negative feedback involving Nanog and T

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Acknowledgements

We thank R Benezra, S Choe, NG Copeland, R Eckner, D Melton, K Miyazono, G Tiscornia, and S Yamanaka for reagents; D Buscher, C Kintner, I Oishi, J Sonoda, and A Tashiro for helpful suggestions; H Pineda, T Chapman, and H Juguilon for technical assistance; and M-F Schwarz for help with this manuscript. AS, TM, and KN received support from the Japan Society for the Promotion of Science, and AR and CR-E from the Fundación Inbiomed, Spain. We are also indebted for support to the Salk Institute, the Lookout Fund, the G Harold and Leila Y Mathers Charitable Foundation, and the National Institutes of Health.

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Authors and Affiliations

  1. Salk Institute for Biological Studies, La Jolla, CA, USA

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  2. Laboratory of Molecular Neuroscience, Nara Institute of Science and Technology, Ikoma, Japan

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  3. Research Unit for Organ Regeneration, Center for Developmental Biology, Kobe, Japan

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  4. Center of Regenerative Medicine, Barcelona, Spain

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

  5. Graduate School of Biological Sciences, Nara Institute of Science and Technology, Takayama, Ikoma, Japan

    Atsushi Suzuki, Ángel Raya, Yasuhiko Kawakami, Masanobu Morita, Takaaki Matsui, Kinichi Nakashima, Fred H Gage, Concepción Rodríguez-Esteban & Juan Carlos Izpisúa Belmonte

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  1. Atsushi Suzuki
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Correspondence to Juan Carlos Izpisúa Belmonte.

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Suzuki, A., Raya, Á., Kawakami, Y. et al. Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification. Nat Rev Cardiol 3 (Suppl 1), S114–S122 (2006). https://doi.org/10.1038/ncpcardio0442

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