Cell sheet technology for regeneration of esophageal mucosa

Abstract

The progress of tissue-engineering technology has realized development of new therapies to treat various disorders by using cultured cells. Cell- and tissue-based therapies have been successfully applied to human patients, and several tissue-engineered products have been approved by the regulatory agencies and are commercially available. In the review article, we describe our experience of development and clinical application of cell sheet-based regenerative medicine. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been shown to be useful for removal of gastrointestinal neoplasms with less invasiveness compared with open surgery, especially in esophageal surgery. However, postoperative inflammation and stenosis are major complications observed after intensive mucosal resection. Therefore, we have developed novel regenerative medicine to prevent such complications and promote wound healing of esophageal mucosa after EMR or ESD. Transplantable oral mucosal epithelial cell sheets were fabricated from patients' own oral mucosa. Immediately after EMR or ESD, fabricated autologous cell sheets were endoscopically transplanted to the ulcer sites. We performed a preclinical study with a canine model. In human clinical settings, cell culture and cell sheet fabrication were performed in clean rooms according to good manufacturing practice guidelines, and pharmaceutical drugs were used as supplements to culture medium in place of research regents used in animal study. We believe that cell-based regenerative medicine would be useful to improve quality of life of patients after EMR or ESD.

Keywords: Cell sheet; Endoscopic resection; Esophageal stenosis; Good manufacturing practice; Oral mucosa.

Figure 1

Transplantable oral mucosal epithelial cell sheet. A: Swine buccal oral mucosal tissue taken by punch biopsy; B: Human oral mucosal epithelial cell sheet harvested from temperature-responsive cell culture insert; C: Cultured human oral mucosal epithelial cells just become confluent on the surface of temperature responsive culture insert; D: The oral mucosal epithelial cells cultured for more than 5 d.

Figure 2

Transplantation of oral mucosal epithelial cell sheets on esophageal ulcer surface in animal model. A: Swine esophageal ulcer after endoscopic mucosal resection (EMR); B: Swine oral mucosal epithelial cell sheet transplanted on esophageal ulcer after EMR; C: Swine esophageal ulcer after endoscopic submucosal dissection (ESD); D: Two swine oral mucosal epithelial cell sheets transplanted on esophageal ulcer after ESD.