Of Mice and Men and Metaplasia

etaplasia, the process in which one type of adult Mtissue replaces another, is a consequence of chronic tissue injury. In the esophagus, gastroesophageal reflux disease (GERD) is the condition that chronically injures the squamous epithelium and causes its replacement by the intestinal-type, columnar epithelium of Barrett’s esophagus. The cell of origin for this columnar metaplasia remains unknown, but a number of candidates have been proposed. For example, GERD might cause mature esophageal squamous cells to change into columnar cells (transdifferentiation) or stimulate immature esophageal progenitor cells (in the squamous epithelium or in the ducts of esophageal submucosal glands) to differentiate abnormally into columnar cells (transcommitment). It also has been suggested that Barrett’s metaplasia results when progenitor cells in the gastric cardia or residual embryonictype cells at the gastroesophageal junction migrate proximally to repair GERD-damaged squamous epithelium. Finally, it has been proposed that circulating stem cells from the bone marrow might be recruited to the GERDdamaged esophagus, where they differentiate into columnar cells. Animal models have been used to explore all of these hypotheses. Animal models of Barrett’s esophagus have used dogs, pigs, rats and mice, and most have involved surgical manipulations that induce GERD to produce a Barrett’s-like, intestinal metaplasia. Unfortunately, all animal models of human disease have limitations. Large animals such as dogs and pigs are expensive and are not easily manipulated at the genetic level. Rats and mice are less expensive and more readily manipulated genetically, but the rodent foregut structure differs substantially from the human. Unlike humans, rats and mice have a squamous-lined forestomach, and their esophagus is lined by a stratified squamous epithelium that is keratinized, and that lacks stromal papillae and submucosal glands. Esophageal surgery is technically more demanding in mice than in rats, and mice have higher surgical mortality rates and lower rates of metaplasia development than rats do. Consequently, rats have been used most frequently as animal models for Barrett’s esophagus. Genetic engineering is far more readily accomplished in mice than in rats, however. Lineage tracing techniques might be especially useful for identifying the Barrett’s cell of origin, and the sophisticated genetic engineering that would be required for such studies can be performed readily in C57Bl/6J mice. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Terabe et al report results of their studies on the development of esophageal columnar metaplasia in C57Bl/6J mice subjected to 3 different GERD-inducing operations: (1) esophagogastrojejunostomy (EGJ) in which the jejunum is connected side-to-side to the junction between