Barrett's Esophagus and Progenitor Cells at the Squamous-Columnar Junction
Columnar metaplasia including Barrett’s esophagus (BE) is considered as a precursor lesion of esophageal adenocarcinoma, which has seen a 600% fold increase in incidence for the last three decades. BE occurs exclusively at the esophageal-gastro junction where the stratified squamous epithelium transitions into simple columnar cell.
In patients with BE, the junction moves anteriorly, and the columnar epithelium is expanded, meanwhile gaining intestinal differentiation characteristics. Significantly, the cell-of-origin of the metaplastic columnar epithelium remains controversial. Here, the researchers identify a novel pseudostratified epithelium maintained by p63+ve basal progenitor cells at the junction.
Their preliminary data suggest that the unique epithelium serves as the origin for the metaplastic epithelium in multiple mouse models. The data further indicate that Wnt signaling promotes metaplastic changes at the squamous-columnar junction. The researchers therefore hypothesize that the novel pseudostratified columnar epithelium is the cell-of-origin for Barrett’s metaplasia and that Wnt signaling promotes metaplastic pathogenesis.
The researchers will test the hypothesis with three specific aims: (1) further test that the unique pseudostratified columnar population is the cell-of-origin for BE, (2) test the hypothesis that inhibition of Wnt signaling blocks BE development from the pseudostratified columnar epithelium, and (3) model the human BE pathogenic process with human embryonic stem cells-derived basal progenitor cells of the columnar epithelium.
The researchers have established a robust in vitro system to induce the differentiation of human embryonic stem cells towards basal cell fate. In this aim, they will use this system to understand the mechanism driving the abnormal differentiation of basal cells during BE development. Findings from this project will throw important insights into early pathogenesis of BE and provide potential therapeutic targets for BE treatment.