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Stem Cells. 2018 Jun;36(6):822-833. doi: 10.1002/stem.2794. Epub 2018 Feb 14.

Fine Tuning of Canonical Wnt Stimulation Enhances Differentiation of Pluripotent Stem Cells Independent of β-Catenin-Mediated T-Cell Factor Signaling.

Chen J1,2,3, Nefzger CM1,2,3, Rossello FJ2, Sun YBY1, Lim SM1,2,3, Liu X1,2,3, de Boer S1,3, Knaupp AS1,2,3, Li J1, Davidson KC2, Polo JM1,2,3, Barberi T2,4.

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Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia.
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.


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 glycogen synthase kinase-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 subthreshold 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. Stem Cells 2018;36:822-833.


Cardiac; Cell signaling; Differentiation; Neural differentiation; Pluripotent stem cells


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