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

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

Onderzoeksoutput: Article

Samenvatting

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.

Originele taal-2English
Artikelnummer6137
Aantal pagina's14
TijdschriftScientific Reports
Volume11
Nummer van het tijdschrift1
DOI's
StatusPublished - 17 mrt 2021

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