Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus

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Abstract
Barrett’s oesophagus—a metaplasia that can be induced by persistent acid reflux, and predisposes patients to oesophageal cancer—arises from a population of basal cells at the gastro-oesophageal junction. Barrett's metaplasia occurs at the gastro-oesophageal junction, sometimes as a result of persistent acid reflux, and predisposes patients to oesophageal cancer. There has been some debate over which cells generate Barrett's oesophagus. Jianwen Que and colleagues now identify a population of basal cells at the gastro-oesophageal junction that give rise to Barrett's metaplasia in mice. Data from human samples suggest the same population of cells gives rise to Barrett's metaplasia in humans. In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy1,2,3, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown1,2,3. In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells4. 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 cells5,6,7,8. 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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