Activin-nodal signaling is involved in propagation of mouse embryonic stem cells
Activin-nodal signaling is involved in propagation of mouse embryonic stem cells
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DOI：
10.1242/jcs.03296
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Ogawa, Kazuya;Saito, Akira;Miyazono, Kohei
胚胎干细胞是一种自我更新的细胞，能够保持分化为所有类型细胞的多能性。由于ES细胞具有在再生医学中提供多种组织的潜力，因此人们对控制ES细胞这些独特特性的生长因子的鉴定非常感兴趣。然而，控制ES细胞增殖的信号通路在很大程度上仍不清楚。由于转化生长因子β超家族成员参与了早期胚胎发育过程，我们研究了它们在ES细胞自我更新中的作用。Smad7或SB-431542抑制激活素-节点-转化生长因子β信号通路可显著降低ES细胞的增殖，而不降低ES的多能性。相反，Smad6对骨形态发生蛋白(BMP)信号的抑制没有表现出这种作用，这表明激活素节点-转化生长因子β信号是ES细胞增殖所必需的，而不是BMP信号。在无血清培养中，添加重组激活素或Nodal，但不添加转化生长因子β或BMP，可显著促进ES细胞的增殖，而不影响其多能性。我们还发现，在无血清培养的ES细胞中，激活素-节点信号以自分泌的方式被结构性激活，并且SB-431542抑制这种内源性信号会降低无血清条件下ES细胞的增殖。这些发现表明，内源性激活的激活素-节点信号的自分泌环促进了ES细胞的自我更新。
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 (TGF beta) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGF beta 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-TGF beta signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGF beta 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.