The Lung and Esophagus: Developmental and Regenerative Overlap

Abstract

Lung and esophageal development and organogenesis involve a complex interplay of signaling pathways and transcriptional factors. Once the lung and esophagus do separate, their epithelial proliferation and differentiation programs share certain common properties that may fuel adaptive responses to injury and subsequent regeneration. Lung and esophageal tissue organogenesis and regeneration provide perspectives on squamous cell cancers and adenocarcinomas in each tissue.

Keywords: Sox2; Trp63; development; esophagus; lung; regeneration.

Figure 1.. Patterning of the Anterior Foregut to Generate the Lung and Esophagus.

Multiple signal transduction pathways including Wnt, Bmp, and Shh are essential for proper patterning of the anterior foregut endoderm into esophageal and lung progenitors. A distinct dorsal-ventral polarity is generated through the combined action of Wnt and Bmp signaling and through other regulators [Barx1, retinoic acid (RA), Gli2/3, Osr1/2]. This results in Sox2 expression being highest in the dorsal endoderm with Nkx2.1 expression restricted to the ventral endoderm.

Figure 2.. Cellular Composition of the Trachea and Large Airways Compared with the Esophagus.

(A) The trachea and large main-stem bronchi of the mouse comprise a pseudostratified epithelium containing the cell lineages shown. Basal cells act as resident stem cells that can regenerate lost secretory and multiciliated epithelia after injury either directly or indirectly (broken arrows). This is regulated, in part, through active Notch signaling. (B) The esophagus contains a true stratified squamous epithelium with basal cells capable (purple) of generating differentiated lineages (suprabasal cells and superficial squamous epithelial cells) (black arrows). Such cells are also referred to as keratinocytes. Notch signaling is important in the switch from proliferative basal cells to differentiated suprabasal cells.

Figure 3.. Hierarchical Comparison between Airway and Esophageal Basal Cells and Their Progeny.

While esophageal and airway basal cells express similar markers (Sox2, Trp63, Krt5), their differentiated progeny differ between the two organs. In the airway, basal cells generate secretory and multiciliated epithelium as well as more specialized epithelial cells such as goblet and neuroendocrine cells. In the esophagus, basal cells generate the stratified epithelium through a multistep process including a classic transient amplifying stage before conversion into fully differentiated luminal keratinocytes. Critical marker genes including transcription factors and keratins are noted for each lineage.