Wnt/β-catenin promotes gastric fundus specification in mice and humans

Nature. 2017 Jan 12;541(7636):182-187. doi: 10.1038/nature21021. Epub 2017 Jan 4.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Patterning
  • Cell Differentiation
  • Cell Lineage
  • Drug Discovery / methods
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelium / embryology
  • Epithelium / metabolism
  • Female
  • Gastric Fundus / cytology
  • Gastric Fundus / embryology
  • Gastric Fundus / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Organoids / cytology
  • Organoids / embryology
  • Organoids / metabolism
  • Parietal Cells, Gastric / cytology
  • Parietal Cells, Gastric / metabolism
  • Pluripotent Stem Cells / cytology
  • SOXB1 Transcription Factors / metabolism
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / metabolism
  • Trans-Activators / metabolism
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway* / genetics
  • beta Catenin / agonists
  • beta Catenin / metabolism*

Substances

  • Homeodomain Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Trans-Activators
  • Wnt Proteins
  • beta Catenin
  • pancreatic and duodenal homeobox 1 protein