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First published online December 20, 2006
doi: 10.1242/10.1242/jcs.03296

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Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells

Kazuya Ogawa^1,*, Akira Saito^2,*, Hisanori Matsui¹, Hiroshi Suzuki², Satoshi Ohtsuka¹, Daisuke Shimosato^1,3, Yasuyuki Morishita², Tetsuro Watabe², Hitoshi Niwa^1,3, and Kohei Miyazono^2,4,

¹ Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
² Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
³ Department of Developmental and Regenerative Medicine, Graduate School of Medicine, Kobe University, 7-5-1, Kusunokicho, Chuo-ku, Kobe 650-0017, Japan
⁴ Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455, Japan

Authors for correspondence (e-mail: niwa{at}cdb.riken.jp; miyazono-ind{at}umin.ac.jp)

Accepted 10 October 2006

Embryonic stem (ES) cells are self-renewing cells that maintain pluripotency to differentiate into all types of cells. Because of their potential to provide a variety of tissues for use in regenerative medicine, there is great interest in the identification of growth factors that govern these unique properties of ES cells. However, the signaling pathways controlling ES cell proliferation remain largely unknown. Since transforming growth factor ß (TGFß) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGFß signaling by Smad7 or SB-431542 dramatically decreased ES cell proliferation without decreasing ES pluripotency. By contrast, inhibition of bone morphogenetic protein (BMP) signaling by Smad6 did not exhibit such effects, suggesting that activin-Nodal-TGFß signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGFß or BMP, significantly enhanced ES cell propagation without affecting pluripotency. We also found that activin-Nodal signaling was constitutively activated in an autocrine fashion in serum-free cultured ES cells, and that inhibition of such endogenous signaling by SB-431542 decreased ES cell propagation in serum-free conditions. These findings suggest that endogenously activated autocrine loops of activin-Nodal signaling promote ES cell self-renewal.

Key words: Embryonic stem cell, Self-renewal, Propagation, TGFß superfamily signaling, Activin-Nodal, Serum-free

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