title: Wnt/β-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells.
abstract: In both mice and humans, pluripotent stem cells (PSCs) exist in at least two distinct states of pluripotency, known as the naïve and primed states. Our understanding of the intrinsic and extrinsic factors that enable PSCs to self-renew and to transition between different pluripotent states is important for understanding early development. In mouse embryonic stem cells (mESCs), Wnt proteins stimulate mESC self-renewal and support the naïve state. In human embryonic stem cells (hESCs), Wnt/β-catenin signaling is active in naïve-state hESCs and is reduced or absent in primed-state hESCs. However, the role of Wnt/β-catenin signaling in naïve hESCs remains largely unknown. Here, we demonstrate that inhibition of the secretion of Wnts or inhibition of the stabilization of β-catenin in naïve hESCs reduces cell proliferation and colony formation. Moreover, we show that addition of recombinant Wnt3a partially rescues cell proliferation in naïve hESCs caused by inhibition of Wnt secretion. Notably, inhibition of Wnt/β-catenin signaling in naïve hESCs did not cause differentiation. Instead, it induced primed hESC-like proteomic and metabolic profiles. Thus, our results suggest that naïve hESCs secrete Wnts that activate autocrine or paracrine Wnt/β-catenin signaling to promote efficient self-renewal and inhibit the transition to the primed state.
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98109; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Zhuojin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Robitaille
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98109; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Berndt
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Davidson
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Fischer
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Julie
authors.initials: J
authors.lastname: Mathieu
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98109; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Potter
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98109.
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
authors.affiliation: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98109; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98109; rtmoon@uw.edu.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D017209:Apoptosis; D052160:Benzothiazoles / Q000494:pharmacology; D015415:Biomarkers; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000187:drug effects / Q000235:genetics; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D040901:Proteomics / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D052160:Benzothiazoles; D015415:Biomarkers; D006575:Heterocyclic Compounds, 3-Ring; C000611186:IWP-2 compound; D034741:RNA, Small Interfering; C544261:XAV939
keywords: Wnt/β-catenin signaling; human embryonic stem cells; naïve pluripotency; naïve-to-primed transition; self-renewal