Fine Tuning of Canonical Wnt Stimulation Enhances Differentiation Of Pluripotent Stem Cells Independent of β-Catenin-Mediated TCF Signaling.
pubmed: wnt1 2018-02-06
Summary:
Fine Tuning of Canonical Wnt Stimulation Enhances Differentiation Of Pluripotent Stem Cells Independent of β-Catenin-Mediated TCF Signaling.
Stem Cells. 2018 Feb 02;:
Authors: Chen J, Nefzger CM, Rossello FJ, Sun YBY, Lim SM, Liu X, de Boer S, Knaupp AS, Li J, Davidson KC, Polo JM, Barberi T
Abstract The canonical Wnt/β-catenin pathway is crucial for early embryonic patterning, tissue homeostasis and regeneration. While canonical Wnt/β-catenin stimulation has been used extensively to modulate pluripotency and differentiation of pluripotent stem cells (PSCs), the mechanism of these two seemingly opposing roles has not been fully characterized and is currently largely attributed to activation of nuclear Wnt target genes. Here, we show that low levels of Wnt stimulation via ectopic expression of Wnt1 or administration of GSK-3 inhibitor CHIR99021 significantly increases PSC differentiation into neurons, cardiomyocytes and early endodermal intermediates. Our data indicate that enhanced differentiation outcomes are not mediated through activation of traditional Wnt target genes but by β-catenin's secondary role as a binding partner of membrane bound cadherins ultimately leading to the activation of developmental genes. In summary, fine-tuning of Wnt signaling to sub-threshold levels for detectable nuclear β-catenin function appears to act as a switch to enhance differentiation of PSCs into multiple lineages. Our observations highlight a mechanism by which Wnt/β-catenin signaling can achieve dosage dependent dual roles in regulating self-renewal and differentiation. This article is protected by copyright. All rights reserved.
PMID: 29396901 [PubMed - as supplied by publisher]