Origin of Barrett's Epithelium: Esophageal Submucosal Glands

Abstract

The origin of the progenitor cell for Barrett's esophagus remains a major unsolved mystery. Understanding the source of this progenitor may improve strategies to prevent the development of esophageal adenocarcinoma. Esophageal submucosal glands (ESMGs) and ducts may serve as a potential source of progenitor cells that respond to esophageal injury. Through the use of human histologic and molecular analysis, ESMGs and ducts have been described in physical continuity with areas of columnar esophagus, and shared mutations have been described between ESMG ducts and Barrett's esophagus. Acinar ductal metaplasia, associated with carcinogenesis in other organs, occurs within ESMGs with human esophageal injury and esophageal adenocarcinoma. By using atypical animal models, a squamous epithelial defect well above the gastroesophageal junction healed to columnar epithelium and continuity of ESMG ducts was noted in the new epithelium. Increased proliferation in ESMGs and ducts in response to injury also has been noted in human beings and animals.

Figure 1

Proposed role of ESMGs in normal and abnormal healing of the esophagus, and the markers used to distinguish the cell types/structures involved in both. (A) Top: Schematic of the following: normal state on the left with normal ESMG under healthy squamous epithelium, then damage in the center with significant epithelial damage with ulceration, and ESMG response on the right with acinar ductal metaplasia replacing normal mucinous acini within the ESMG. (A) Bottom: The concept of ESMG and duct response in normal healing to neosquamous epithelium on the left, or, under different conditions, abnormal healing to columnar epithelium (right). (B) Table representing reported markers of different components represented in the figure including squamous epithelium, columnar epithelium, the basal and luminal layers of the main ducts, intercalated ducts within ESMGs, and the mucinous cells of normal ESMGs. Of note, ESMG ducts share markers with both squamous and columnar epithelium.