TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling
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TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling. / Funa, Nina Sofi; Mjoseng, Heidi Katharina; Raineri, Silvia; Esen, Deniz; Egeskov-Madsen, Anuska la Rosa; Quaranta, Roberto; Jørgensen, Mette Christine; Hansen, Maria Skjøtt; van Cuyl Kuylenstierna, Jonas; Jensen, Kim Bak; Miao, Yi; Garcia, K Christopher; Seymour, Philip A; Serup, Palle.
In: Stem Cell Reports, 16.06.2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling
AU - Funa, Nina Sofi
AU - Mjoseng, Heidi Katharina
AU - Raineri, Silvia
AU - Esen, Deniz
AU - Egeskov-Madsen, Anuska la Rosa
AU - Quaranta, Roberto
AU - Jørgensen, Mette Christine
AU - Hansen, Maria Skjøtt
AU - van Cuyl Kuylenstierna, Jonas
AU - Jensen, Kim Bak
AU - Miao, Yi
AU - Garcia, K Christopher
AU - Seymour, Philip A
AU - Serup, Palle
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2024/6/16
Y1 - 2024/6/16
N2 - Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation protocols. Here we used human embryonic stem cells (hESCs) to interrogate how exogenous factors modulate endogenous signaling events during specification of foregut endoderm lineages. We find that transforming growth factor β1 (TGF-β1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-β1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-β1-treated cells refractory to Wnt signaling. Subsequently, TGF-β1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-β1 treatment and Wnt inhibition during pancreatic specification reproducibly and robustly enhance INSULIN + cell yield across hESC lines. This modification of widely used differentiation protocols will enhance pancreatic β cell yield for cell-based therapeutic applications.
AB - Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation protocols. Here we used human embryonic stem cells (hESCs) to interrogate how exogenous factors modulate endogenous signaling events during specification of foregut endoderm lineages. We find that transforming growth factor β1 (TGF-β1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-β1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-β1-treated cells refractory to Wnt signaling. Subsequently, TGF-β1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-β1 treatment and Wnt inhibition during pancreatic specification reproducibly and robustly enhance INSULIN + cell yield across hESC lines. This modification of widely used differentiation protocols will enhance pancreatic β cell yield for cell-based therapeutic applications.
U2 - 10.1016/j.stemcr.2024.05.010
DO - 10.1016/j.stemcr.2024.05.010
M3 - Journal article
C2 - 38942030
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
ER -
ID: 396937108