Esophageal Organoids from Human Pluripotent Stem Cells Delineate Sox2 Functions during Esophageal Specification

Cell Stem Cell. 2018 Oct 4;23(4):501-515.e7. doi: 10.1016/j.stem.2018.08.008. Epub 2018 Sep 20.


Tracheal and esophageal disorders are prevalent in humans and difficult to accurately model in mice. We therefore established a three-dimensional organoid model of esophageal development through directed differentiation of human pluripotent stem cells. Sequential manipulation of bone morphogenic protein (BMP), Wnt, and RA signaling pathways was required to pattern definitive endoderm into foregut, anterior foregut (AFG), and dorsal AFG spheroids. Dorsal AFG spheroids grown in a 3D matrix formed human esophageal organoids (HEOs), and HEO cells could be transitioned into two-dimensional cultures and grown as esophageal organotypic rafts. In both configurations, esophageal tissues had proliferative basal progenitors and a differentiated stratified squamous epithelium. Using HEO cultures to model human esophageal birth defects, we identified that Sox2 promotes esophageal specification in part through repressing Wnt signaling in dorsal AFG and promoting survival. Consistently, Sox2 ablation in mice causes esophageal agenesis. Thus, HEOs present a powerful platform for modeling human pathologies and tissue engineering.

Keywords: Sox2; esophagus; foregut; organoid.

Publication types

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

MeSH terms

  • Adolescent
  • Animals
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Esophageal Diseases / metabolism*
  • Esophageal Diseases / pathology*
  • Esophagus / cytology*
  • Esophagus / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Organoids / metabolism*
  • Pluripotent Stem Cells / metabolism*
  • SOXB1 Transcription Factors / metabolism*


  • SOX2 protein, human
  • SOXB1 Transcription Factors