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TGF-ß modulates cell fate in human ES cell-derived foregut endoderm by inhibiting Wnt and BMP signaling.
Funa, Nina Sofi; Mjoseng, Heidi Katharina; de Lichtenberg, Kristian Honnens; 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.
Afiliação
  • Funa NS; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: nina.funa@astrazeneca.com.
  • Mjoseng HK; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • de Lichtenberg KH; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Raineri S; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Esen D; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Egeskov-Madsen AR; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Quaranta R; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Jørgensen MC; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Hansen MS; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • van Cuyl Kuylenstierna J; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • Jensen KB; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Miao Y; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 9
  • Garcia KC; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 9
  • Seymour PA; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
  • Serup P; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen,
Stem Cell Reports ; 19(7): 973-992, 2024 Jul 09.
Article em En | MEDLINE | ID: mdl-38942030
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 ß1 (TGF-ß1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-ß1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-ß1-treated cells refractory to Wnt signaling. Subsequently, TGF-ß1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-ß1 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 ß cell yield for cell-based therapeutic applications.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Proteínas Morfogenéticas Ósseas / Endoderma / Via de Sinalização Wnt / Células-Tronco Embrionárias Humanas Limite: Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diferenciação Celular / Proteínas Morfogenéticas Ósseas / Endoderma / Via de Sinalização Wnt / Células-Tronco Embrionárias Humanas Limite: Humans Idioma: En Revista: Stem Cell Reports Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos