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

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 pro...

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Bibliographic Details
Published in:	Cell stem cell Vol. 23; no. 4; pp. 501 - 515.e7
Main Authors:	Trisno, Stephen L., Philo, Katherine E.D., McCracken, Kyle W., Catá, Emily M., Ruiz-Torres, Sonya, Rankin, Scott A., Han, Lu, Nasr, Talia, Chaturvedi, Praneet, Rothenberg, Marc E., Mandegar, Mohammad A., Wells, Susanne I., Zorn, Aaron M., Wells, James M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 04-10-2018
Subjects:	esophagus foregut organoid Sox2 foregut Sox2 esophagus organoid
Online Access:	Get full text
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Summary:	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. [Display omitted] •Sequential Wnt, RA, and BMP signaling are required to pattern dorsal anterior foregut•Cultured dorsal anterior foregut spheroids develop into esophageal organoids (HEOs)•HEOs contain basal esophageal progenitors and stratified squamous epithelium•Sox2 is sufficient to repress the respiratory fate by suppressing Wnt signaling Trisno et al. have generated human esophageal organoids (HEOs) through the directed differentiation of pluripotent stem cells. HEOs contain esophageal progenitors and a differentiated stratified squamous epithelium. Using HEOs to model foregut development revealed that SOX2 regulates NKX2-1 through modulation of Wnt signaling.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS S.L.T and J.M.W primarily conceived the experimental design, performed and analyzed the experiments, and co-wrote the manuscript. K.E.D.P, S.R.T., K.W.M, E.M.C, L.H. performed experiments. S.R.T. and S.I.W. advised and performed the organotypic epithelial raft experiments. S.A.R and A.M.Z performed the Xenopus experiments. M.A.M generated the SOX2 CRISPRi cell line and provided knockdown analysis. M.E.R provided the human esophageal biopsy RNA samples for comparison to in vitro derived organoids and cultures. P.C., T.N., and S.L.T. conducted and analyzed the RNA-seq experiments. All authors contributed to the writing and/or editing of the manuscript.
ISSN:	1934-5909 1875-9777
DOI:	10.1016/j.stem.2018.08.008