Open AccessFine Tuning of Canonical Wnt Stimulation Enhances Differentiation of Pluripotent Stem Cells Independent of β‐Catenin‐Mediated T‐Cell Factor Signaling
Author(s) -
Chen Joseph,
Nefzger Christian M.,
Rossello Fernando J.,
Sun Yu B.Y.,
Lim Sue Mei,
Liu Xiaodong,
de Boer Suzan,
Knaupp Anja S.,
Li Jinhua,
Davidson Kathryn C.,
Polo Jose M.,
Barberi Tiziano
Publication year - 2018
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2794
Subject(s) - wnt signaling pathway , biology , microbiology and biotechnology , induced pluripotent stem cell , stem cell , gsk 3 , catenin , cellular differentiation , beta catenin , embryonic stem cell , cell polarity , lrp6 , induced stem cells , signal transduction , cell , genetics , gene
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. S tem C ells 2018;36:822–833