title: Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells.
abstract: Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. 1). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. d.tenberge@erasmusmc.nl
authors.forename: Derk
authors.initials: D
authors.lastname: ten Berge
authors.forename: Dorota
authors.initials: D
authors.lastname: Kurek
authors.forename: Tim
authors.initials: T
authors.lastname: Blauwkamp
authors.forename: Wouter
authors.initials: W
authors.lastname: Koole
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Elif
authors.initials: E
authors.lastname: Eroglu
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Siu
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D011994:Recombinant Proteins; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse