title: Endogenous WNT signals mediate BMP-induced and spontaneous differentiation of epiblast stem cells and human embryonic stem cells.
abstract: Therapeutic application of human embryonic stem cells (hESCs) requires precise control over their differentiation. However, spontaneous differentiation is prevalent, and growth factors induce multiple cell types; e.g., the mesoderm inducer BMP4 generates both mesoderm and trophoblast. Here we identify endogenous WNT signals as BMP targets that are required and sufficient for mesoderm induction, while trophoblast induction is WNT independent, enabling the exclusive differentiation toward either lineage. Furthermore, endogenous WNT signals induce loss of pluripotency in hESCs and their murine counterparts, epiblast stem cells (EpiSCs). WNT inhibition obviates the need to manually remove differentiated cells to maintain cultures and improves the efficiency of directed differentiation. In EpiSCs, WNT inhibition stabilizes a pregastrula epiblast state with novel characteristics, including the ability to contribute to blastocyst chimeras. Our findings show that endogenous WNT signals function as hidden mediators of growth factor-induced differentiation and play critical roles in the self-renewal of hESCs and EpiSCs.
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kurek
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Neagu
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Melodi
authors.initials: M
authors.lastname: Tastemel
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Tüysüz
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Harmen J G
authors.initials: HJG
authors.lastname: van de Werken
authors.affiliation: Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Reinier
authors.initials: R
authors.lastname: van der Linden
authors.affiliation: Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.affiliation: Erasmus MC Center for Biomics, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Wilfred F J
authors.initials: WFJ
authors.lastname: van IJcken
authors.affiliation: Institute of Stem Cell Research, German Research Center for Environmental Health, Helmholtz Center Munich, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Micha
authors.initials: M
authors.lastname: Drukker
authors.affiliation: Erasmus MC Stem Cell Institute, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address: d.tenberge@erasmusmc.nl.
authors.forename: Derk
authors.initials: D
authors.lastname: Ten Berge
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005855:Germ Layers / Q000166:cytology*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D010641:Phenotype; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D059467:Transcriptome; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D051153:Wnt Proteins