Journal
CELL STEM CELL
Volume 28, Issue 8, Pages 1411-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.03.019
Keywords
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Categories
Funding
- TELEVIE
- Fondation contre le Cancer [FCC/ULB 2018-067]
- Fonds pour la formation a la recherche dans l'industrie et dans l'agriculture (FRIA)
- Worldwide Cancer Research [1611-92]
- region Wallonie-Bruxelles (ARC consolidator)
- FNRS [F4538.16 MIS]
- WELBIO [FRFS-WELBIO-CR-2017S-01]
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This study reveals that activation of the Hedgehog pathway in esophageal cells can lead to dedifferentiation into embryonic-like esophageal progenitors, with a subset of these cells eventually undergoing squamous-to-columnar conversion, associated with chromatin remodeling and the appearance of Sox9. Sox9 is shown to be required for columnar conversion but not for dedifferentiation, providing insight into the mechanisms by which esophageal cells might initiate columnar metaplasia.
Columnar metaplasia of the esophagus is the main risk factor for esophageal adenocarcinoma. There is a lack of evidence to demonstrate that esophageal progenitors can be the source of columnar metaplasia. In this study, using transgenic mouse models, lineage tracing, single-cell RNA sequencing, and transcriptomic and epigenetic profiling, we found that the activation of the Hedgehog pathway in esophageal cells modifies their differentiation status in vivo. This process involves an initial step of dedifferentiation into embryonic-like esophageal progenitors. Moreover, a subset of these cells undergoes full squamous-to-columnar conversion and expresses selected intestinal markers. These modifications of cell fate are associated with remodeling of the chromatin and the appearance of Sox9. Using a conditional knockout mouse, we show that Sox9 is required for columnar conversion but not for the step of dedifferentiation. These results provide insight into the mechanisms by which esophageal cells might initiate columnar metaplasia.
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