The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal–esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus

Abstract

The esophagus and trachea are tubular organs that initially share a single common lumen in the anterior foregut. Several models have been proposed to explain how this single-lumen developmental intermediate generates two tubular organs. However, new evidence suggests that these models are not comprehensive. I will first briefly review these models and then propose a novel ‘splitting and extension’ model based on our in vitro modeling of the foregut separation process. Signaling molecules (e.g., SHHs, WNTs, BMPs) and transcription factors (e.g., NKX2.1 and SOX2) are critical for the separation of the foregut. Intriguingly, some of these molecules continue to play essential roles during the transition of simple columnar into stratified squamous epithelium in the developing esophagus, and they are also closely involved in epithelial maintenance in the adults. Alterations in the levels of these molecules have been associated with the initiation and progression of several esophageal diseases and cancer in adults.

Development and stem cells of the esophagus

“…Previously three models have been proposed to describe how the esophagus is separated from the trachea, including: (1) The outgrowth model in which the trachea extends with the lung primordium from the early foregut, (2) the watershed model in which a yet-to-be identified mesenchymal condensation serves as a wedge to split the anterior foregut into the trachea and esophagus, and (3) the septation model where epithelial cells at the dorsal–ventral midline make contact across the midline of the lumen and fuse to form a septum [1]. Recent evidence, however, has suggested that none of these models fully accounts for tracheal-esophageal separation.…”

The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury

“…Meanwhile, the mesenchymal cells surrounding the nascent esophagus proliferate and differentiate into muscularis mucosa and the MP, with networks of blood vessels and nerves running throughout. Although controversies remain regarding the cellular origin of striated muscle and regulation of esophageal muscular development, the use of genetic mouse models has revealed that multiple genes, transcription factors, and signal pathways are involved in this process . Specifically, the cell surface receptor Cdo is required for setting up the striated‐smooth muscle boundary.…”

“…Although controversies remain regarding the cellular origin of striated muscle and regulation of esophageal muscular development, the use of genetic mouse models has revealed that multiple genes, transcription factors, and signal pathways are involved in this process. 1,7 Specifically, the cell surface receptor Cdo is required for setting up the striated-smooth muscle boundary. The bHLH transcription factor Myf5 is required for striated muscle differentiation.…”

Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog/Gli Is Required for Tracheoesophageal Separation

“…Between 25-35 days of human gestation, the fetal gut tube separates into the distinct trachea and esophagus (Billmyre et al, 2015;Que, 2015). Disruptions in this process result in lifethreatening defects that impair neonatal respiration and feeding, including esophageal atresia (EA), tracheal atresia (TA), and/or tracheoesophageal fistula (TEF) (Brosens et al, 2014).…”