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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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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

Original languageEnglish
Article number6137
JournalScientific Reports
Issue number1
PublishedDec 2021

Bibliographical note

Funding Information: This work was supported by the Methusalem grant of Vrije Universiteit Brussel granted to K.S. D.D. was a PhD fellow of Research Foundation—Flanders (Fonds voor Wetenschappelijk Onderzoek, FWO—Vlaanderen). A.K. is a PhD fellow of FWO (Strategisch Basisonderzoek). The authors would like to thank Geoffrey Duque for the technical assistance with LSM800 confocal microscope and the NXTGNT team for performing the mRNA-sequencing. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


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.

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