Transitional Basal Cells at the Squamous-Columnar Junction Generate Barrett's Oesophagus

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Barrett Esophagus / genetics
  • Barrett Esophagus / metabolism
  • Barrett Esophagus / pathology*
  • CDX2 Transcription Factor / genetics
  • CDX2 Transcription Factor / metabolism
  • Cell Lineage*
  • Cell Tracking
  • Epithelial Cells / pathology*
  • Epithelium / pathology*
  • Esophagitis / metabolism
  • Esophagitis / pathology
  • Esophagogastric Junction / metabolism
  • Esophagogastric Junction / pathology*
  • Gastroesophageal Reflux
  • Goblet Cells / metabolism
  • Goblet Cells / pathology
  • Humans
  • Keratin-5 / metabolism
  • Keratin-7 / metabolism
  • Metaplasia / metabolism
  • Metaplasia / pathology
  • Mice
  • Phosphoproteins / metabolism
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Trans-Activators / metabolism

Substances

  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Keratin-5
  • Keratin-7
  • Phosphoproteins
  • Trans-Activators
  • Trp63 protein, mouse