A prospective study of 555 individuals (59% with BE) evaluated by endoscopy found columnar islands in 34% of instances.48 In a study of esophagectomy specimens from 131 individuals with esophageal squamous cell carcinoma in Japan, columnar epithelial islands were identified in 57% of specimens.49 It is noteworthy that in patients with Become, columnar islands often are located a Coelenterazine considerable distance proximal to the Barretts section, so these islands are likely to emerge due to an etiology other than guide extension of columnar metaplasia.48 One potential source of these columnar or squamous islands is the esophageal submucosal glands (ESMGs) (Number 3). Open in CD36 a separate window Figure 3. In a patient with Become who had an island of columnar epithelium in squamous mucosa, an ESMG and duct is present directly beneath the columnar island. Finally, we discuss shortcomings in current diagnostic criteria for Become that have important medical implications. or by medicines harmful to parietal cells, the death of parietal cells appears to be accompanied by transdifferentiation of main cells into proliferative cells that expresses trefoil element 2 (TFF2, also known as spasmolytic polypeptide).12-15 In mice with acute injury, there is evidence that development of spasmolytic polypeptide-expressing metaplasia (SPEM) occurs when mature chief cells dedifferentiate and re-enter the cell cycle. This is a 3-stage process during which the cells: shut Coelenterazine down mTORC1 signaling, which enables autophagy to recycle cellular material for use in the synthesis of fresh cell structures; begin to express genes associated with metaplasia, such as and null (via de novo methylation in the promoter region.37 This observation provides evidence that direct transdifferentiation (without a dedifferentiation event) can occur during embryonic development, but it is not obvious that a related process occurs in adults. However, a reversal of this process in the adult esophagus might result in columnar metaplasia. Could Cells Native to the Esophagus Provide Become 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 Barretts metaplasia. For example, scanning electron microscopy of biopsy specimens taken from the junction between squamous and Barretts epithelium exposed a distinct cell type, with prominent intercellular ridges (a Coelenterazine feature of squamous cells) and microvilli (a feature of columnar cells).40,41 These distinctive cells might have developed via reprogramming of pluripotent progenitor cells in the squamous epithelium. In rats with ulcerative reflux esophagitis, experts found the nuclei of proliferative esophageal basal cells located adjacent to esophageal ulcerations to have decreased levels of SOX2 (a marker of basal progenitor cells in adult squamous esophagus) and improved levels of SOX9 (a marker of progenitor cells in adult intestine, liver, pancreas, and gastric corpus that also is indicated in the embryonic esophagus), compared to non-ulcerated cells in the same esophagus.42 Reflux esophagitis can therefore reprogram squamous progenitor cells to express columnar genes, but those cells retained their squamous morphology and would therefore not be considered metaplastic. In support of a role for reprogramming of progenitor cells by GERD in the development of Become, telomerase-immortalized human being esophageal squamous cells revealed in vitro to acid, bile salts or nitric oxide (a harmful molecule created when diet nitrate encounters acid in refluxed gastric juice) down-regulate manifestation of transcription factors involved in squamous cell differentiation such as p63 and SOX2,43,44 and up-regulate manifestation of Coelenterazine columnar and intestinal transcription factors such as SOX9, CDX2, and FOXA2.44-46 Acid and bile salts also can activate signaling pathways in esophageal squamous cells (such as hedgehog and BMP4) that control activity of transcription factors that regulate development and cell phenotypes.45,47 Furthermore, long term exposure of telomerase-immortalized esophageal squamous cells with acidic bile salts produces alterations in morphology characteristic of columnar cells.44 However, these in vitro manipulations of squamous cells have not resulted in their transformation into goblet cells, which are typically found in Barretts metaplasia. Esophageal submucosal glands Endoscopists often observe discrete islands of squamous epithelium within a field of Barretts metaplasia or, conversely, islands of columnar epithelium proximal to the squamo-columnar junction (SCJ). A prospective study of 555 individuals (59% with Become).