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Cell Stem Cell. 2018 Oct 4;23(4):516-529.e5. doi: 10.1016/j.stem.2018.08.009. Epub 2018 Sep 20.

3D Modeling of Esophageal Development using Human PSC-Derived Basal Progenitors Reveals a Critical Role for Notch Signaling.

Author information

1
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA; Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA.
2
Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
3
Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
5
Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
6
Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA.
7
Department of Ophthalmology, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
8
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands; Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium.
9
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
10
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA.
11
Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's, PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal.
12
Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
13
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10032, USA; Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: jq2240@cumc.columbia.edu.

Abstract

Pluripotent stem cells (PSCs) could provide a powerful system to model development of the human esophagus, whose distinct tissue organization compared to rodent esophagus suggests that developmental mechanisms may not be conserved between species. We therefore established an efficient protocol for generating esophageal progenitor cells (EPCs) from human PSCs. We found that inhibition of TGF-ß and BMP signaling is required for sequential specification of EPCs, which can be further purified using cell-surface markers. These EPCs resemble their human fetal counterparts and can recapitulate normal development of esophageal stratified squamous epithelium during in vitro 3D cultures and in vivo. Importantly, combining hPSC differentiation strategies with mouse genetics elucidated a critical role for Notch signaling in the formation of this epithelium. These studies therefore not only provide an efficient approach to generate EPCs, but also offer a model system to study the regulatory mechanisms underlying development of the human esophagus.

KEYWORDS:

BMP; NOTCH; TGF-ß; WNT; basal cells; esophagus; human embryonic stem cells; human-induced pluripotent stem cell; organoids

PMID:
30244870
PMCID:
PMC6282026
[Available on 2019-10-04]
DOI:
10.1016/j.stem.2018.08.009

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