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Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4

2012; National Academy of Sciences; Volume: 109; Issue: 12 Linguagem: Inglês

10.1073/pnas.1118777109

1091-6490

Kathryn C. Davidson, Allison Adams, Jamie M. Goodson, Circe E. McDonald, Jennifer Potter, Jason D. Berndt, Travis L. Biechele, Russell J. Taylor, Randall T. Moon,

Tissue Engineering and Regenerative Medicine

Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of β-catenin signaling, which led us to postulate that Wnt/β-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses β-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates β-catenin signaling in hESCs. Using a fluorescent reporter of β-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated β-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/β-catenin signaling in the differentiation rather than self-renewal of hESCs.