Regenerative Medicine Strategies for Esophageal Repair

Abstract

Pathologies that involve the structure and/or function of the esophagus can be life-threatening. The esophagus is a complex organ comprising nonredundant tissue that does not have the ability to regenerate. Currently available interventions for esophageal pathology have limited success and are typically associated with significant morbidity. Hence, there is currently an unmet clinical need for effective methods of esophageal repair. The present article presents a review of esophageal disease along with the anatomic and functional consequences of each pathologic process, the shortcomings associated with currently available therapies, and the latest advancements in the field of regenerative medicine with respect to strategies for esophageal repair from benchtop to bedside.

FIG. 1.

The human esophagus: (A) The majority of the esophagus resides in the mediastinum anteriorly to the vertebral column and the descending aorta and posteriorly to the trachea, lungs, and heart. The esophagus has three natural narrowings: at the cricoid cartilage, at the tracheal bifurcation, and as it passes through the diaphragm. (B) The esophagus and the stomach are separated by the gastroesophageal sphincter. While the esophagus is lined by a stratified squamous epithelium, the stomach is lined by a columnar epithelium. (C) The esophagus comprises four concentric layers: starting from the lumen, the mucosa (stratified squamous epithelium), submucosa (glands and connective tissue), muscularis externa (two layers: circumferential and longitudinal), and adventitia (connective tissue). UES, upper esophageal sphincter; LES, lower esophageal sphincter. Color images available online at www.liebertpub.com/teb

FIG. 2.

Increase in incidence of esophageal adenocarcinoma and obesity: (A) Esophageal adenocarcinoma has one of the highest rates of increased incidence among neoplastic diseases. (B) The increase in the incidence rate of esophageal adenocarcinoma is only matched by that observed in obesity. *Data for 2005–2020 are extrapolated. Figures adapted from Pohl and Welch 2005 and Sturm et al., 2004. Color images available online at www.liebertpub.com/teb

FIG. 3.

Esophageal cancer staging: The TNM (tumor, node, and metastasis) staging system takes into consideration a number of variables, including tumor invasion (T), the presence or absence of metastatic disease (M), and nodal invasion (N). Tumor staging will determine the clinical approach to the disease. Staging for adenocarcinoma of the esophagus is shown as an example. HGD, high-grade dysplasia. Figure adapted from Pennathur et al. Color images available online at www.liebertpub.com/teb

FIG. 4.

Esophageal congenital abnormalities: The most common congenital abnormalities of the esophagus include (A) esophageal atresia and (B) tracheoesophageal fistula. These conditions result in mechanical obstruction of the esophagus and are incompatible with life. Detection occurs shortly after birth. Color images available online at www.liebertpub.com/teb

FIG. 5.

Esophageal epithelium: (A) The architecture of the esophageal epithelium includes papillary structures located at regular intervals (PBL) separated by flat interpapillary zones (IBL). The basal cells comprise a heterogeneous population of epithelial cells with cells located in the IBL constituting the stem cell compartment (blue) and transit-amplifying cells residing in the PBL (orange). Epibasal layers (purple) are undergoing differentiation and can no longer divide. The arrow indicates the direction of differentiation. (B) When isolated and cultured, esophageal stem cells have shown organoid-forming capacity and show similar organization to native tissues through (C) hematoxylin and eosin staining and (D) Cytokeratin 14 and (E) Cytokeratin 13 stains. Native tissue shown in inset for comparison (D, E). Color images available online at www.liebertpub.com/teb

FIG. 6.

Esophageal mucosal resection in the rat model: (A) Mucosal resection in the rat is performed by exposing the esophagus around the trachea and performing a mucosectomy through a horizontal incision in the muscularis layer of the esophagus. (B) Once the mucosa is removed, an extracellular matrix (ECM)-derived biomaterial is delivered in situ to facilitate constructive tissue remodeling. (C) Masson's trichrome stain of native esophageal mucosa (arrow) and (D) remodeled esophageal mucosa after biomaterial-mediated repair showing intact keratinized epithelium (arrowhead). Color images available online at www.liebertpub.com/teb

FIG. 7.

Levrat model: (A, B) An esophagoduodenal anastomosis is performed by ligating the gastroesophageal junction and (C) anastomosing the distal end of the esophagus to the jejunum, creating a patent conduit that induces gastroduodenojejunal reflux. (D, E) The gastroesophageal sphincter is ligated and remains attached to the stomach (arrow head). The anastomosis between the distal end of the esophagus and the jejunum forms a patent conduit that allows free retrograde flow (double arrow). Color images available online at www.liebertpub.com/teb

FIG. 8.

Esophageal preservation in human patients after endomucosal resection in the setting of superficial cancer: The current standard of care for esophageal neoplasia is esophagectomy, a procedure associated with high morbidity and mortality. As an alternative, Badylak et al. have implemented an entirely endoscopic method for removal of the mucosa and submucosa with subsequent placement of a biologic scaffold to promote constructive mucosal remodeling and minimize stricture formation in the setting of superficial cancer. To date, the method has been successfully used to treat eight human patients. (A) Diagnostic biopsy showing high-grade dysplasia. (B) Postoperative biopsy showing replacement of the ECM scaffold with mature, differentiated squamous epithelium. Representative endoscopic views of each stage in the procedure and follow-up: (C) Muscularis externa being exposed during inversion and resection of the entire sleeve of mucosal and submucosal layers (arrow). (D) Stent placed to gently compress the ECM scaffold (arrow) against the exposed muscularis layer. (E) Thirteen-month follow-up showing complete coverage of the resected area by normal esophageal epithelium without stricture formation. Color images available online at www.liebertpub.com/teb