Gastroenterology

Gastroenterology

Volume 157, Issue 2, August 2019, Pages 349-364.e1
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Pathogenesis and Cells of Origin of Barrett's Esophagus

https://doi.org/10.1053/j.gastro.2019.03.072Get rights and content

In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.

Section snippets

Transdifferentiation

A potential mechanism of BE pathogenesis involves transdifferentiation, in which fully differentiated esophageal squamous cells change into fully differentiated columnar cells—either directly (without undergoing a cell division) or indirectly (via cell division).8 Although differentiated cells once were considered immutable, studies have demonstrated that differentiated cells can be reprogrammed to acquire characteristics of immature progenitor cells.9 Many types of mature cells have the

Transcommitment

Transcommitment is the process in which immature progenitor cells that are able to proliferate and differentiate into different cell types are reprogrammed to alter their normal pattern of differentiation.20 Transcommitment shares late features of transdifferentiation through paligenosis, a process that starts with dedifferentiation of mature cells into progenitor-like cells before they re-differentiate abnormally. In contrast, transcommitment starts with immature progenitor cells that

Could Cells Native to the Esophagus Provide Barrett’s Esophagus Progenitor Cells?

There are several lines of evidence that could support either transdifferentiation of esophageal squamous cells, through paligenosis, or transcommitment of esophageal progenitor cells in the pathogenesis of Barrett’s metaplasia. For example, scanning electron microscopy of biopsy specimens taken from the junction between squamous and Barrett’s epithelium revealed a distinct cell type, with prominent intercellular ridges (a feature of squamous cells) and microvilli (a feature of columnar cells).

Stomach Cells as Barrett’s Esophagus Progenitor Cells

Although Barrett’s metaplasia is considered intestinal because it contains goblet cells and expresses some intestinal markers, it also contains gastric-type cells that express gastric proteins, such as claudin18 and TFF2.66, 67 Quante et al68 found that Lgr5+ epithelial progenitor cells in the gastric cardia might be cells of origin for Barrett’s-like metaplasia in mice with chronic inflammation in the esophagus and forestomach. In these mice, an Epstein-Barr virus promoter (ED-L2) promotes

Barrett’s Metaplasia as a Wound-Healing Process

Regardless of which progenitor cells give rise to BE, the metaplastic process is assumed to be initiated by esophageal injury from GERD. Reflux esophagitis often leads to esophageal ulceration that is bordered proximally by squamous epithelium and distally by gastric epithelium, with ESMGs and their ducts lying underneath the ulcer crater. Cells from any of these locations might contribute to esophageal re-epithelization initially via a wound healing process, with GERD-induced reprogramming

Cardiac Mucosa, Intestinal Metaplasia With Goblet Cells, and Barrett’s Esophagus

The gastric cardia is believed to be lined, to a variable extent, by cardiac mucosa—a glandular lining comprising mucus-secreting, gastric foveolar-type cells with no goblet cells and few or no parietal cells (Figure 5). However, there is considerable indirect evidence to support a hypothesis, proposed by Chandrasoma88 in 1997, that cardiac mucosa is not normal but an acquired, GERD-induced metaplasia, and that cardiac mucosa is the precursor of intestinal metaplasia in BE.89 For example,

Acknowledgments

All authors contributed equally to the preparation of this manuscript.

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work was supported by the National Institutes of Health (DK113144, DK100342, DK120650 to J.Q.; DK098528, DK118022 to K.S.G.; DK63621, DK103598, K11139 to R.F.S. and S.J.S.) and by Baylor Scott & White Research Institute (R.F.S. and S.J.S.).

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