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  • TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling.

TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling.

Stem cell reports (2024-06-29)
Nina Sofi Funa, Heidi Katharina Mjoseng, Kristian Honnens de Lichtenberg, Silvia Raineri, Deniz Esen, Anuska la Rosa Egeskov-Madsen, Roberto Quaranta, Mette Christine Jørgensen, Maria Skjøtt Hansen, Jonas van Cuyl Kuylenstierna, Kim Bak Jensen, Yi Miao, K Christopher Garcia, Philip A Seymour, Palle Serup
ABSTRACT

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.

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