Altered BMP signaling in human EA/TEF

Introduction: The organogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) remains unknown. The fistula tract appears to develop from a non-branching trifurcation of the embryonic lung bud. The non-branching growth of the fistula differs from the other lung buds and suggests a deficiency in Bone Morphogenetic Protein (BMP) signaling, since BMP's are critical to proper lung development and branching. Methods: With IRB approval, portions of newborn human proximal esophageal pouch and distal fistula samples were recovered at the time of surgical repair of EA/TEF. The tissues were processed for immunohistochemistry. Commercially available fetal tissues were used as controls. Results: BMP ligands (BMP2, −4, −7) and receptors (BMPRIA, BMPRIB, BMPRII) were all present in these tissues. BMP2 and BMP4 were expressed in the epithelial/sub-epithelial gland region of the proximal pouch, as well as in normal esophagus, whereas they were absent in fistula and trachea. BMP7, however, showed strong staining only in the glands of the trachea. BMPRIA was negative in the fistula, but positive in the tracheal epithelium. BMPRIB was positive in submucosal glands of the fistula and trachea. BMPRII was expressed at the base of the fistula and proximal pouch epithelium. Conclusions: Thus, the submucosa of the fistula appears to maintain a trachea-like BMP signaling pattern, which would explain its lack of esophageal motility and lack of lung branching.