Fine tuning of canonical Wnt stimulation enhances differentiation of pluripotent stem cells independent of β-catenin-mediated T-cell factor signalling

Research output: Contribution to journalArticle

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 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.
LanguageEnglish
Pages822-833
Number of pages12
JournalStem Cells
Volume36
Issue number6
DOIs
StatePublished - Jun 2018

Keywords

  • cell signaling
  • differentiation
  • neural differentiation
  • pluripotent stem cells
  • cardiac

Cite this

@article{2a08b4cfd5b74aefa2dfb8148daeab15,
title = "Fine tuning of canonical Wnt stimulation enhances differentiation of pluripotent stem cells independent of β-catenin-mediated T-cell factor signalling",
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 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.",
keywords = "cell signaling, differentiation, neural differentiation, pluripotent stem cells, cardiac",
author = "Joseph Chen and Nefzger, {Christian M.} and Fernando Rossello and Sun, {Yu B.Y.} and Lim, {Sue Mei} and Xiaodong Liu and {De Boer}, Suzan and Knaupp, {Anja S.} and Jinhua Li and Davidson, {Kathryn C.} and Polo, {Jose M.} and Tiziano Barberi",
year = "2018",
month = "6",
doi = "10.1002/stem.2794",
language = "English",
volume = "36",
pages = "822--833",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press, Inc",
number = "6",

}

TY - JOUR

T1 - Fine tuning of canonical Wnt stimulation enhances differentiation of pluripotent stem cells independent of β-catenin-mediated T-cell factor signalling

AU - Chen,Joseph

AU - Nefzger,Christian M.

AU - Rossello,Fernando

AU - Sun,Yu B.Y.

AU - Lim,Sue Mei

AU - Liu,Xiaodong

AU - De Boer,Suzan

AU - Knaupp,Anja S.

AU - Li,Jinhua

AU - Davidson,Kathryn C.

AU - Polo,Jose M.

AU - Barberi,Tiziano

PY - 2018/6

Y1 - 2018/6

N2 - 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.

AB - 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.

KW - cell signaling

KW - differentiation

KW - neural differentiation

KW - pluripotent stem cells

KW - cardiac

U2 - 10.1002/stem.2794

DO - 10.1002/stem.2794

M3 - Article

VL - 36

SP - 822

EP - 833

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T2 - Stem Cells

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SN - 1066-5099

IS - 6

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