Esophageal regenerative therapy using cell sheet technology

Abstract

We have been conducting research on esophageal regenerative therapy using cell sheet technology. In particular, in the endoscopic field, we have pushed forward clinical research on endoscopic transplantation of cultured autologous oral mucosal epithelial cell sheets to esophageal ulcer after endoscopic submucosal dissection (ESD). We started research in this direction using animal models in 2004 and performed clinical research in 2012 in collaboration with Nagasaki University and Karolinska Institute. Although in full-circumferential cases it was difficult to prevent esophageal stricture after ESD, there were no complications and stricture could be suppressed. The cell sheet technology is still in its infancy. However, we are convinced that it has a high potential for application in various areas of gastrointestinal science. In this review, we focus on the pre-clinical and clinical trial results obtained and on the theoretical aspects of (1) stricture prevention, (2) esophageal tissue engineering research, and (3) endoscopic transplantation, and review the esophageal regenerative therapy by cell sheet technology.

A Scarless Healing Tale: Comparing Homeostasis and Wound Healing of Oral Mucosa With Skin and Oesophagus

“…Autologous oral mucosal keratinocytes were endoscopically implanted after oesophageal resection in a porcine model, resulting in accelerated re-epithelialisation and wound healing ( Sakurai et al, 2007 ). On a “bench to bedside” approach, tissue-engineered autologous oral epithelial cell sheets and full-thickness substitutes were endoscopically transplanted into an oesophageal ulcer immediately after a large endoscopic submucosal dissection, showing excellent results with no cases of dysphagia or stricture formation ( Ohki et al, 2006 , 2012 , 2015 ; Arakelian et al, 2018 ; Ohki and Yamamoto, 2020 ). The first clinical trial using cell sheet technology for oesophageal reconstruction in Europe used cell sheets from autologous oral epithelial cells, transplanted right after endoscopic submucosal dissection of Barrett’s neoplasms, resulting in decreased risk and extent of strictures ( Jonas et al, 2016 ).…”

Recent Advances of Biomedical Materials for Prevention of Post-ESD Esophageal Stricture

“…Cells and the extracellular matrix within the sheet can form interconnections with tissues through multiple pathways or interactions, enhancing adhesive strength between the cell sheet and the esophageal wound. As far as previous studies are concerned, cell sheets contain oral mucosal epithelial cell (OMEC) sheets ( Ohki and Yamamoto 2020 ), compound cell sheets composed of OMECs and small intestinal submucosa (SIS) ( Wei et al, 2009 ), and autologous skin epidermal cell sheets ( Kanai et al, 2012 ). Ohki et al (2012 ) discovered the promising potential of autologous OMEC transplantation to prevent esophageal stricture after ESD the earliest ( Figure 7 ).…”

“…(D) Cell sheets composed of OMECs were transplanted immediately on the esophageal defect under endoscopy after ESD. Reproduced from Ohki and Yamamoto (2020 ). Copyright (2020), with permission from Elsevier.…”

Development of Multilayer Mesenchymal Stem Cell Cell Sheets

“…It allows the detachment of the cells, as a whole cell sheet, without the use of enzymes such as trypsin [89]. The cell sheets can be transferred on to another surface (dishes, organs, or cell sheets), because the extracellular matrix as well as the cell-cell contact were preserved [90,91]. Cell-cell contact and communication are very important for the organs' function [92,93].…”