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Nature. 2017 Oct 26;550(7677):529-533. doi: 10.1038/nature24269. Epub 2017 Oct 12.

Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.

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Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Institute for Laboratory Medicine, Fuzhou General Hospital, Fuzhou, Fujian 350025, China.
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
Ascendas Genomics Inc., Zhongshan, Guangdong 529437, China.
School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Institute for Cancer Medicine, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China.
Department of Pathology, University Medical Center of Princeton at Plainsboro, Plainsboro, New Jersey 08536, USA.
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Department of Radiation Oncology, Columbia University Medical Center, New York, New York 10032, USA.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
Department of Basic Medicine, Tianjin Institute of Respiratory Diseases, Haihe Clinical College of Tianjin Medical University, Tianjin 300350, China.
Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina 27707, USA.


In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.

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