Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm

Abstract Low differentiation propensity towards a targeted lineage can significantly hamper the utility of individual human pluripotent stem cell (hPSC) lines in biomedical applications. Here, we use monolayer and micropatterned cell cultures, as well as transcriptomic profiling, to investigate how...

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Autores principales:	Dominika Dziedzicka, Mukul Tewary, Alexander Keller, Laurentijn Tilleman, Laura Prochazka, Joel Östblom, Edouard Couvreu De Deckersberg, Christina Markouli, Silvie Franck, Filip Van Nieuwerburgh, Claudia Spits, Peter W. Zandstra, Karen Sermon, Mieke Geens
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9e385811ab3744d7a6a8dfcfa4c06319
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spelling	oai:doaj.org-article:9e385811ab3744d7a6a8dfcfa4c063192021-12-02T16:31:17ZEndogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm10.1038/s41598-021-85447-42045-2322https://doaj.org/article/9e385811ab3744d7a6a8dfcfa4c063192021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85447-4https://doaj.org/toc/2045-2322Abstract Low differentiation propensity towards a targeted lineage can significantly hamper the utility of individual human pluripotent stem cell (hPSC) lines in biomedical applications. Here, we use monolayer and micropatterned cell cultures, as well as transcriptomic profiling, to investigate how variability in signalling pathway activity between human embryonic stem cell lines affects their differentiation efficiency towards definitive endoderm (DE). We show that endogenous suppression of WNT signalling in hPSCs at the onset of differentiation prevents the switch from self-renewal to DE specification. Gene expression profiling reveals that this inefficient switch is reflected in NANOG expression dynamics. Importantly, we demonstrate that higher WNT stimulation or inhibition of the PI3K/AKT signalling can overcome the DE commitment blockage. Our findings highlight that redirection of the activity of Activin/NODAL pathway by WNT signalling towards mediating DE fate specification is a vulnerable spot, as disruption of this process can result in poor hPSC specification towards DE.Dominika DziedzickaMukul TewaryAlexander KellerLaurentijn TillemanLaura ProchazkaJoel ÖstblomEdouard Couvreu De DeckersbergChristina MarkouliSilvie FranckFilip Van NieuwerburghClaudia SpitsPeter W. ZandstraKaren SermonMieke GeensNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dominika Dziedzicka Mukul Tewary Alexander Keller Laurentijn Tilleman Laura Prochazka Joel Östblom Edouard Couvreu De Deckersberg Christina Markouli Silvie Franck Filip Van Nieuwerburgh Claudia Spits Peter W. Zandstra Karen Sermon Mieke Geens Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
description	Abstract Low differentiation propensity towards a targeted lineage can significantly hamper the utility of individual human pluripotent stem cell (hPSC) lines in biomedical applications. Here, we use monolayer and micropatterned cell cultures, as well as transcriptomic profiling, to investigate how variability in signalling pathway activity between human embryonic stem cell lines affects their differentiation efficiency towards definitive endoderm (DE). We show that endogenous suppression of WNT signalling in hPSCs at the onset of differentiation prevents the switch from self-renewal to DE specification. Gene expression profiling reveals that this inefficient switch is reflected in NANOG expression dynamics. Importantly, we demonstrate that higher WNT stimulation or inhibition of the PI3K/AKT signalling can overcome the DE commitment blockage. Our findings highlight that redirection of the activity of Activin/NODAL pathway by WNT signalling towards mediating DE fate specification is a vulnerable spot, as disruption of this process can result in poor hPSC specification towards DE.
format	article
author	Dominika Dziedzicka Mukul Tewary Alexander Keller Laurentijn Tilleman Laura Prochazka Joel Östblom Edouard Couvreu De Deckersberg Christina Markouli Silvie Franck Filip Van Nieuwerburgh Claudia Spits Peter W. Zandstra Karen Sermon Mieke Geens
author_facet	Dominika Dziedzicka Mukul Tewary Alexander Keller Laurentijn Tilleman Laura Prochazka Joel Östblom Edouard Couvreu De Deckersberg Christina Markouli Silvie Franck Filip Van Nieuwerburgh Claudia Spits Peter W. Zandstra Karen Sermon Mieke Geens
author_sort	Dominika Dziedzicka
title	Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
title_short	Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
title_full	Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
title_fullStr	Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
title_full_unstemmed	Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
title_sort	endogenous suppression of wnt signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9e385811ab3744d7a6a8dfcfa4c06319
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Endogenous suppression of WNT signalling in human embryonic stem cells leads to low differentiation propensity towards definitive endoderm

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