A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling.
A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling.
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DOI：
10.1002/stem.1944
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Huang TS;Li L;Moalim-Nour L;Jia D;Bai J;Yao Z;Bennett SA;Figeys D;Wang L
经典Wnt信号通路在维持胚胎干细胞（ESC）自我更新或诱导分化和谱系特化中的不同作用的机制尚不清楚。在这项研究中，我们首次证明了人类胚胎干细胞（hESCs）响应Wnt信号的自我更新与分化主要由两层调控回路决定，包括β-catenin，E-cadherin，PI 3 K/Akt和Slug以时间依赖性方式。β-catenin的短期上调不会导致hESC中T细胞因子（TCF）-eGFP Wnt报告基因的激活。相反，它增强了细胞膜上的E-钙粘蛋白表达，从而通过E-钙粘蛋白相关的PI 3 K/Akt信号增强了hESC的自我更新。相反，长期Wnt激活或E-钙粘蛋白细胞内β-连环蛋白结合结构域的缺失诱导TCF-eGFP活性，并通过β-连环蛋白诱导的Slug上调促进hESC分化。Slug表达增强导致E-钙粘蛋白进一步减少，E-钙粘蛋白作为β-连环蛋白“汇”隔离游离的细胞质β-连环蛋白。这种框架的形成加强了hESC从与短期Wnt/β-catenin激活相关的时间自我更新状态转换为最终分化。干细胞2015;33：1419-1433
The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self‐renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self‐renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two‐layer regulatory circuit involving β‐catenin, E‐cadherin, PI3K/Akt, and Slug in a time‐dependent manner. Short‐term upregulation of β‐catenin does not lead to the activation of T‐cell factor (TCF)‐eGFP Wnt reporter in hESCs. Instead, it enhances E‐cadherin expression on the cell membrane, thereby enhancing hESC self‐renewal through E‐cadherin‐associated PI3K/Akt signaling. Conversely, long‐term Wnt activation or loss of E‐cadherin intracellular β‐catenin binding domain induces TCF‐eGFP activity and promotes hESC differentiation through β‐catenin‐induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E‐cadherin that serves as a β‐catenin “sink” sequestering free cytoplasmic β‐catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self‐renewal associated with short‐term Wnt/β‐catenin activation to definitive differentiation. Stem Cells 2015;33:1419–1433