Journal
STEM CELLS
Volume 33, Issue 5, Pages 1419-1433Publisher
WILEY-BLACKWELL
DOI: 10.1002/stem.1944
Keywords
Wnt; beta-Catenin; E-cadherin; Slug; Human embryonic stem cell; Self-renewal; Differentiation
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-111224]
- Heart and Stroke Foundation of Ontario [NA7186]
- Canada Research Chair in Proteomics and Systems Biology
- NSERC [STPGP/396508-2010]
- CIHR [MOP 62826]
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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 beta-catenin, E-cadherin, PI3K/Akt, and Slug in a time-dependent manner. Short-term upregulation of beta-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 beta-catenin binding domain induces TCF-eGFP activity and promotes hESC differentiation through beta-catenin-induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E-cadherin that serves as a beta-catenin sink sequestering free cytoplasmic beta-catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self-renewal associated with short-term Wnt/beta-catenin activation to definitive differentiation.
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