title: FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1.
abstract: Fibroblast growth factors (FGFs) are required to specify hepatic fate within the definitive endoderm through activation of the FGF receptors (FGFRs). While the signaling pathways involved in hepatic specification are well understood, the mechanisms through which FGFs induce hepatic character within the endoderm are ill defined. Here we report the identification of genes whose expression is directly regulated by FGFR activity during the transition from endoderm to hepatic progenitor cell. The FGFR immediate early genes that were identified include those encoding transcription factors, growth factors, and signaling molecules. One of these immediate early genes encodes naked cuticle homolog 1 (NKD1), which is a repressor of canonical WNT (wingless-type MMTV integration site) signaling. We show that loss of NKD1 suppresses the formation of hepatic progenitor cells from human induced pluripotent stem cells and that this phenotype can be rescued by using a pharmacological antagonist of canonical WNT signaling. We conclude that FGF specifies hepatic fate at least in large part by inducing expression of NKD1 to transiently suppress the canonical WNT pathway.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA;
authors.forename: Kirk
authors.initials: K
authors.lastname: Twaroski
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Mallanna
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Jing
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: DiFurio
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Urick
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Program in Regenerative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Duncan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D004707:Endoderm / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008099:Liver / Q000166:cytology / Q000196:embryology; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C449091:NKD1 protein, human; D016222:Fibroblast Growth Factor 2
keywords: FGF signaling; HNF4a; WNT; iPSC-derived hepatocytes; liver development