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

Abstract

In several organ systems the transitional zone between different types of epithelia is a hotspot for pre-neoplastic metaplasia and malignancy1–3. However, the cell-of-origin for the metaplastic epithelium and subsequent malignancy, remains obscure1–3. In the case of Barrett’s oesophagus (BE), intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells4. Based on different experimental models, several alternative cell types have been proposed as the source of the metaplasia, but in all cases the evidence is inconclusive and no model completely mimics BE with the presence of intestinal goblet cells5–8. Here, we describe a novel transitional columnar epithelium with distinct basal progenitor cells (p63+ KRT5+ KRT7+) in the squamous-columnar junction (SCJ) in the upper gastrointestinal tract of the mouse. We use multiple models and lineage tracing strategies to show that this unique SCJ basal cell population serves as a source of progenitors for the transitional epithelium. Moreover, upon ectopic expression of CDX2 these transitional basal progenitors differentiate into intestinal-like epithelium including goblet cells, thus reproducing Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues, including the anorectal junction, and, importantly, at the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (MLE) believed to be a precursor of BE are both characterized by the expansion of the transitional basal progenitor cells. Taken together our findings reveal the presence of a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+ KRT7+ basal cells in this zone are the cell-of-origin for MLE and BE.

The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury

“…The molecular mechanisms underlying this reversed metaplasia and the cell origin are still under investigation. Treatment with acidified media and/or bile salts in vitro mimicking gastroesophageal reflux or using bile acid reflux mouse models have demonstrated the downregulation of squamous transcription factors (e.g., p63 and Sox2), upregulation of columnar (e.g., Sox9), intestinal (e.g., Cdx1 and Cdx2), and mucin (e.g., Foxa2) associated transcription factors, as well as alterations in various signaling pathways that are involved in the development of BE …”

Recent advances in Barrett's esophagus

“…Similarly, a rodent model of BE that overexpresses cytokine IL‐1β found progressive inflammation, metaplasia, and even dysplasia localized at the SCJ . The development of these metaplastic glands was potentiated by bile acids and hypersecretion of gastrin . Recently, Jiang and coworkers identified a multilayered transitional zone in the murine SCJ with a basal layer of cells .…”

Barretts's carcinogenesis

“…(b) Esophago‐jejunostomy without gastrectomy . (c) The esophagogastric junction was side‐to‐side anastomosed to a loop of jejunum …”

“…b); (iii) the esophageal gland duct (Fig. c); (iv) the esophagogastric junction mucosa (Fig. d); (v) the fetal remnant (Fig.…”