Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor
Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor
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DOI：
10.1038/nm979
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发表时间：
2004-01-01
期刊：
影响因子：
82.9
通讯作者：
Brivanlou, AH
中科院分区：
文献类型：
--
作者：
Sato, N;Meijer, L;Brivanlou, AH
人类和小鼠胚胎干细胞(分别为hESCs和MESCs)可以无限期自我更新，同时保持生成所有三种胚层衍生细胞的能力。尽管胚胎干细胞在发育生物学中的重要性及其对组织替代治疗的潜在影响，但胚胎干细胞自我更新的分子机制尚不清楚。在这里，我们证明了规范的Wnt通路的激活足以维持hESCs和MESCs的自我更新。虽然STAT-3信号参与了胚胎干细胞的自我更新，但刺激这一途径并不支持胚胎干细胞的自我更新。相反，我们发现，糖原合成酶激酶-3(GSK-3)的特异性药物抑制剂6-溴吲哚红-3‘-肟(BIO)激活Wnt通路，维持了这两种类型ESCs的未分化表型，并维持了多能状态特异性转录因子Oct-3/4、Rex-1和Nanog的表达。WNT信号在未分化的MESCs中被内源性激活，并在分化后下调。此外，生物介导的Wnt激活在功能上是可逆的，因为化合物的退出会导致hESCs和MESCs的正常多分化程序。这些结果表明，GSK-3特异性抑制剂的使用，如BIO，可能在再生医学中有实际应用。
Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.