title: Wnt/β-catenin promotes gastric fundus specification in mice and humans.
abstract: Despite the global prevalence of gastric disease, there are few adequate models in which to study the fundus epithelium of the human stomach. We differentiated human pluripotent stem cells (hPSCs) into gastric organoids containing fundic epithelium by first identifying and then recapitulating key events in embryonic fundus development. We found that disruption of Wnt/β-catenin signalling in mouse embryos led to conversion of fundic to antral epithelium, and that β-catenin activation in hPSC-derived foregut progenitors promoted the development of human fundic-type gastric organoids (hFGOs). We then used hFGOs to identify temporally distinct roles for multiple signalling pathways in epithelial morphogenesis and differentiation of fundic cell types, including chief cells and functional parietal cells. hFGOs are a powerful model for studying the development of the human fundus and the molecular bases of human gastric physiology and pathophysiology, and also represent a new platform for drug discovery.
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: McCracken
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Eitaro
authors.initials: E
authors.lastname: Aihara
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Martin
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Calyn M
authors.initials: CM
authors.lastname: Crawford
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Broda
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Treguier
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Xinghao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Shannon
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Marshall H
authors.initials: MH
authors.lastname: Montrose
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.|Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wells
mesh_terms: D000818:Animals; D019521:Body Patterning; D002454:Cell Differentiation; D019070:Cell Lineage; D055808:Drug Discovery / Q000379:methods; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D005748:Gastric Fundus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000819:agonists / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; C084010:pancreatic and duodenal homeobox 1 protein