Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells.
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 beta (TGFbeta) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGFbeta 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-TGFbeta signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGFbeta 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.
Ogawa
Kazuya
K
Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
Saito
Akira
A
Matsui
Hisanori
H
Suzuki
Hiroshi
H
Ohtsuka
Satoshi
S
Shimosato
Daisuke
D
Morishita
Yasuyuki
Y
Watabe
Tetsuro
T
Niwa
Hitoshi
H
Miyazono
Kohei
K
D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002678:Chimera; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D055457:Nodal Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D013724:Teratoma; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D016895:Culture Media, Serum-Free; D004149:Dioxoles; D055457:Nodal Protein; C526008:Nodal protein, mouse; D047428:Protein Kinase Inhibitors; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D028341:Activins