scholarly journals A wave of WNT signalling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells

2018 ◽  
Author(s):  
I. Martyn ◽  
A.H. Brivanlou ◽  
E.D. Siggia
Keyword(s):  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Quantitative Model ◽  
Wnt Signalling ◽  
Generic Property ◽  
Bistable System ◽  
Embryonic Patterning ◽  
Model Formation ◽  
Wnt Inhibitors

AbstractLong range signalling by morphogens and their inhibitors define embryonic patterning yet quantitative data and models are rare, especially in humans. Here we use a human embryonic stem cell “gastruloid” system to model formation of the primitive streak (PS) by WNT. In the pluripotent state E-CADHERIN (E-CAD) transduces boundary forces to focus WNT signalling to colony border. Following application of WNT ligand, E-CAD mediates a wave of epithelial-to-mesenchymal (EMT) conversion analogous to PS extension in an embryo. By knocking out the secreted WNT inhibitors active in our system, we show that DKK1 alone controls the extent and duration of patterning. The NODAL inhibitor CERBERUS1 acts downstream of WNT to refine the endoderm versus mesoderm fate choice. Our EMT wave is a generic property of a bistable system with diffusion and a single quantitative model describes both the wave and our knockout data.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominika Dziedzicka ◽  
Mukul Tewary ◽  
Alexander Keller ◽  
Laurentijn Tilleman ◽  
Laura Prochazka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Biomedical Applications ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Wnt Signalling ◽  
Definitive Endoderm ◽  
Human Pluripotent Stem Cell ◽  
Stem Cell Lines ◽  
Differentiation Efficiency ◽  
Individual Human

AbstractLow 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.

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

2020 ◽  
Author(s):  
Dominika Dziedzicka ◽  
Mukul Tewary ◽  
Alexander Keller ◽  
Laurentijn Tilleman ◽  
Laura Prochazka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Biomedical Applications ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Wnt Signalling ◽  
Definitive Endoderm ◽  
Human Pluripotent Stem Cell ◽  
Stem Cell Lines ◽  
Differentiation Efficiency ◽  
Individual Human

SummaryLow 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.

scholarly journals An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

2013 ◽  
Author(s):  
David A Turner ◽  
Jamie Trott ◽  
Penelope Hayward ◽  
Pau Rué ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Es Cells ◽  
Initial Period ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Wnt Signalling ◽  
Dependent Manner ◽  
Cell Fate Decisions ◽  
Mouse Es Cells

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a ?race for fates? in which the neuroectodermal fate has an advantage.

scholarly journals TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency

Development ◽  
2018 ◽  
Vol 145 (4) ◽  
pp. dev161075 ◽  
Author(s):  
Robert A. Sierra ◽  
Nathan P. Hoverter ◽  
Ricardo N. Ramirez ◽  
Linh M. Vuong ◽  
Ali Mortazavi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Stem Cell Pluripotency ◽  
Embryonic Stem Cell Pluripotency

scholarly journals Keeping a lid on nodal: transcriptional and translational repression of nodal signalling

Open Biology ◽  
2016 ◽  
Vol 6 (1) ◽  
pp. 150200 ◽  
Author(s):  
Karuna Sampath ◽  
Elizabeth J. Robertson
Keyword(s):  
Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Transforming Growth Factor ◽  
Sea Urchins ◽  
Embryonic Stem ◽  
Translational Repression ◽  
Embryonic Patterning ◽  
Evolutionarily Conserved ◽  
Stem Cell Pluripotency ◽  
Embryonic Stem Cell Pluripotency

Nodal is an evolutionarily conserved member of the transforming growth factor- β (TGF-β) superfamily of secreted signalling factors. Nodal factors are known to play key roles in embryonic development and asymmetry in a variety of organisms ranging from hydra and sea urchins to fish, mice and humans. In addition to embryonic patterning, Nodal signalling is required for maintenance of human embryonic stem cell pluripotency and mis-regulated Nodal signalling has been found associated with tumour metastases. Therefore, precise and timely regulation of this pathway is essential. Here, we discuss recent evidence from sea urchins, frogs, fish, mice and humans that show a role for transcriptional and translational repression of Nodal signalling during early development.

IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche

2020 ◽  
Author(s):  
Wamaitha SE ◽  
Grybel KJ ◽  
Alanis-Lobato G ◽  
Gerri C ◽  
Ogushi S ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Self Renewal
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