Efficient derivation of embryonic stem cells by inhibition of glycogen synthase kinase-3
Efficient derivation of embryonic stem cells by inhibition of glycogen synthase kinase-3
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DOI：
10.1634/stemcells.2007-0086
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发表时间：
2007-11-01
期刊：
影响因子：
5.2
通讯作者：
Nakano, Toru
中科院分区：
文献类型：
--
作者：
Umehara, Hiroki;Kimura, Tohru;Nakano, Toru
胚胎干细胞（Embryonic stem cells，ES）来源于囊胚的内细胞团（inner cell mass，ICM）。ES细胞作为分化细胞来源的应用为细胞移植治疗带来了巨大的希望。ES细胞衍生的效率受到小鼠遗传变异的影响;也就是说，一些小鼠品系，如C57 BL/6，适合ES细胞衍生，而其他小鼠品系，如BALB/c，则是难治性的。建立一种从不同遗传背景的ES细胞株中建立ES细胞的有效方法，对于在包括人在内的各种哺乳动物中建立ES细胞具有重要意义。虽然已经确定了多种信号通路，包括磷酸肌醇3-激酶（Pl 3 K）/Akt和Wnt/β-连环蛋白，调节ES细胞多能性的维持，但是对于从ICM衍生ES细胞所涉及的信号通路知之甚少。在这项研究中，我们证明，糖原合成酶激酶-3（GSK-3），在Wnt/β-catenin，Hedgehog和Notch信号通路的调节中的关键分子之一的抑制，显着增强ES细胞从C57 BL/6和BALB/c小鼠品系的衍生。相反，Akt信号激活促进ICM的生长，但不增加ES细胞衍生的效率。我们的研究建立了一个有效的手段，ES细胞衍生的药理学抑制GSK-3。
Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of blastocysts. The use of ES cells as a source of differentiated cells holds great promise for cell transplantation therapy. The efficiency of ES cell derivation is affected by genetic variation in mice; that is, some mouse strains, such as C57BL/6, are amenable to ES cell derivation, whereas others, such as BALB/c, are refractory. Developing an efficient method to establish ES cells from strains of various genetic backgrounds should be valuable for derivation of ES cells in various mammalian species, including human. Although it is well-established that various signaling pathways, including phosphoinositide 3-kinase (Pl3K)/Akt and Wnt/beta-catenin, regulate the maintenance of ES cell pluripotency, little is known about the signaling pathways involved in the derivation of ES cells from ICMs. In this study, we demonstrated that inhibition of glycogen synthase kinase-3 (GSK-3), one of the crucial molecules in the regulation of the Wnt/beta-catenin, Hedgehog, and Notch signaling pathways, dramatically augmented ES cell derivation from both C57BL/6 and BALB/c mouse strains. In contrast, Akt signaling activation enhanced the growth of ICM but did not increase the efficiency of ES cell derivation. Our study establishes an efficient means for ES cell derivation by pharmacological inhibition of GSK-3.