Development and stem cells of the esophagus

Abstract

The esophagus is derived from the anterior portion of the developmental intermediate foregut, a structure that also gives rise to other organs including the trachea, lung, and stomach. Genetic studies have shown that multiple signaling pathways (e.g. Bmp) and transcription factors (e.g. SOX2) are required for the separation of the esophagus from the neighboring respiratory system. Notably, some of these signaling pathways and transcription factors continue to play essential roles in the subsequent morphogenesis of the esophageal epithelium which undergoes a simple columnar-to-stratified squamous conversion. Reactivation of the relevant signaling pathways has also been associated with pathogenesis of esophageal diseases that affect the epithelium and its stem cells in adults. In this review we will summarize these findings. We will also discuss new data regarding the cell-of-origin for the striated and smooth muscles surrounding the esophagus and how they are differentiated from the mesenchyme during development.

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

“…The septum separates the tracheal tube and esophagus and generates the trachea ventrally and the esophagus dorsally. This tracheal–esophageal separation occurs at approximately 4–6 weeks of gestation in humans . The failure of this process results in various anomalies such as esophageal atresia with or without tracheoesophageal fistula (EA/TEF).…”

“…Similarly, downregulation of Sox2 in the early foregut leads to EA/TEF . The functions of Sox2 and Nkx2.1 are regulated by several signaling pathways . WNT/β‐catenin signaling pathway plays a crucial role in specifying Nkx2.1 + respiratory endoderm progenitors during development.…”

Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging

“…We also confirmed the reduction in the number of Sox2+ cells, and the effects produced by the partial depletion in tissues previously described as dependent on the activity of stem and progenitor Sox2+ cells. We inspected the testis (Arnold et al, 2011), esophagus and trachea (Zhang et al, 2017) and found that GCV‐treated mice were showing atrophic seminiferous tubules (Figure S2), a feature previously described for these transgenic mice after acute depletion of Sox2+ cells (Arnold et al, 2011) and a frequent event during aging (Gosden, Richardson, Brown, & Davidson, 1982), and a decreased epithelial cellularity in esophagus and trachea that corresponded with a reduced number of Sox2+ cells (Figure S2). …”

A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance

“…Around embryonic days 9.5-11.0, live imaging reveals a saddle-like structure that separates esophagus and stomach from trachea and lung. 47 Genetic models suggest that transcription factors (eg, SOX2, NKX2.1) and signaling molecules (eg, Noggin, Wnt2/2b) are critical for establishing esophagus from foregut, 48 after which esophageal lining changes from columnar into squamous epithelium under control of transcription factors like p63 and SOX2. A p63 gene deletion prevents this epithelial change, and SOX2 down-regulation causes esophageal progenitor cells to differentiate abnormally into mucin-secreting cells.…”

“…A p63 gene deletion prevents this epithelial change, and SOX2 down-regulation causes esophageal progenitor cells to differentiate abnormally into mucin-secreting cells. 48,49 Bmp signaling in the esophagus also is required for normal development of squamous epithelium. 50 In the stomach, multiple signaling pathways (eg, Bmp, Notch, Wnt) and transcription factors (eg, BARX1, NKX2.5, and GATA3) mediate the development of gastric glandular epithelia.…”