Update on Foregut Molecular Embryology and Role of Regenerative Medicine Therapies

Abstract

Esophageal atresia (OA) represents one of the commonest and most severe developmental disorders of the foregut, the most proximal segment of the gastrointestinal (GI) tract (esophagus and stomach) in embryological terms. Of intrigue is the common origin from this foregut of two very diverse functional entities, the digestive and respiratory systems. OA appears to result from incomplete separation of the ventral and dorsal parts of the foregut during development, resulting in disruption of esophageal anatomy and frequent association with tracheo-oesophageal fistula. Not surprisingly, and likely inherent to OA, are associated abnormalities in components of the enteric neuromusculature and ultimately loss of esophageal functional integrity. An appreciation of such developmental processes and associated defects has not only enhanced our understanding of the etiopathogenesis underlying such devastating defects but also highlighted the potential of novel corrective therapies. There has been considerable progress in the identification and propagation of neural crest stem cells from the GI tract itself or derived from pluripotent cells. Such cells have been successfully transplanted into models of enteric neuropathy confirming their ability to functionally integrate and replenish missing or defective enteric nerves. Combinatorial approaches in tissue engineering hold significant promise for the generation of organ-specific scaffolds such as the esophagus with current initiatives directed toward their cellularization to facilitate optimal function. This chapter outlines the most current understanding of the molecular embryology underlying foregut development and OA, and also explores the promise of regenerative medicine.

Keywords: enteric nervous system; esophageal atresia; foregut development; stem cell; tissue engineering; tracheo-esophageal fistula.

Figure 1

Compartmentalization of the foregut. At E9.5 in the mouse, the lung buds start to arise from the common foregut tube (dashed line; top). According to the Outgrowth model (bottom left), the trachea extends from the foregut tube at the level where lung buds develop (curved arrow). The Watershed model suggests that both developing trachea and esophagus elongate (arrows) from the diverging point (dashed line; middle). According to the Septation model (bottom right), a septum is formed from lateral ridges of mesenchyme, which moves up along the longitudinal axis of the common foregut tube separating the trachea and esophagus (arrow).

Figure 2

Regional specification of the developing gut. Specification of the developing gut is determined initially by a concentration gradient of retinoic acid along the anterior–posterior axis.

Figure 3

Dorsoventral patterning of the developing foregut endoderm. The dorsal (yellow) and ventral (blue) endoderm express Sox2 and Nkx2.1, respectively. NOGGIN, produced by the surrounding mesenchyme (orange), regulates the expression of Sox2 in the dorsal foregut endoderm by directly activating Sox2 expression and indirectly inhibiting BMP4, which in turn inhibits Sox2. Ventrally, Wnt2/2b signaling activates the expression of Nkx2.1 in the ventral foregut endoderm, and WNT signaling also inhibits Nkx2.1 expression in the dorsal foregut endoderm. The mutual inhibition activity of Nkx2.1 and Sox2 create an expression gradient of these two genes, thereby allowing the separation of the two organs.