日本語 The Esophagus Group
Regenerative Medical Therapy Based On Transplantation of Autologous Oral Mucosal Epithelial Cell Sheets
About 11,000 people die of esophageal cancer annually in Japan. It is a cancer more susceptible to recurrence than other gastrointestinal tract organs and is therefore one of the difficult cancers to treat. There are basically three different methods for treating it: surgery, chemotherapy and radiation therapies. Especially in early esophageal cancer that is confined to the mucosa, endoscopic mucosal resection (EMR) has been the standard treatment method. In this method, first we remove most of the esophagus together with the lymph nodes surrounding it by means of thoracotomy. As a replacement for the removed esophagus, we reform part of the stomach into an elongated tubular shape called a gastric tube. We then connect this tube with the remnant esophagus, either in the mediastinum or in the neck region to create a reconstructed esophagus. Because important organs such as the heart and lungs anatomically exist near the esophagus, this operation is very difficult and highly invasive. Therefore, more extensive application of therapeutic endoscopy for the treatment of esophageal cancer is expected so that a specimen can be taken with the minimum of invasiveness, the purpose being to secure an accurate pathological diagnosis. Also, in recent years, endoscopic submucosal dissection (ESD), which enables a precise diagnosis and a more extensive en-bloc resection compared to conventional EMR, has been developed, and its use is being extended to treat esophageal cancer, following its employment in treating gastric cancer. However, ulcerative esophageal constriction from extensive esophageal ESD may present a serious problem, while constriction after endoscopic excision is very difficult to treat. Patients experiencing constriction are required to receive frequent endoscopic balloon dilatations, which cause deterioration in their quality of life (QOL).
With these issues in mind, we have developed a regenerative treatment method in which we remove pieces of tissue from the autologous oral mucosa, and then produce an oral mucosal epithelial cell sheet by using a temperatureresponsive culture dish. This enables us to endoscopically transplant the cell sheet to the ulcerative surface after ESD. We have already reported the results of our preclinical experiments on large animals. Our clinical research treatment of artificial esophageal ulcerations resulting from EMR, by means of endoscopic transplantation of autologous oral mucosal epithelial cell sheets, was approved by the Ethics Committee of Tokyo Women’s Medical University in 2005. Based on the new Guidelines for Clinical Research Using Human Stem Cells, which took effect on September 1st, 2006, we constructed within our university a GMP-compliant cellprocessing center. The aim of the center is to facilitate a series of procedures from outpatient examination to transplantations held in the endoscopy procedure room. We required about two years of additional preparation following the center’s establishment before we were able to begin clinical applications. We started registration of patients in January 2008 and have treated 10 cases so far; a paper reporting the results is currently submitted. Now our plans include filing an application to conduct treatment based on this advanced method; introducing this treatment method to Nagasaki University under the system known as the "special zone for advanced medical treatments;" and working to promote clinical application research on treating Barretts esophagus that we will carry out jointly with Karolinska Institutet, Sweden.
Fig.1：
Esophageal regenerative medical therapy using cell sheets
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Fig.2：
Cultured oral mucosal epithelial cell sheets
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Researcher Introduction
Department of Surgery, Institute of Gastroenterology /
Institute of Advanced BioMedical Engineering and Science (Joint Appointment),
Assistant Professor Takeshi OHKI
Regenerative treatment of early esophagus cancer using endoscopic submucosal dissection and cultured oral mucosal epithelial cell sheets has now advanced to the level of clinical application. This is the world's first regenerative clinical-based research using digestive organ tissues. The application range resulting from this research is wide indeed. It is expected to be applied not only to endoscopic therapy for cancers in other digestive organs such as the stomach and large intestine, and to esophageal squamous cell cancer (the most common pathological type of esophageal cancer in Japan), but also to Barretts esophagus resulting from gastro-esophageal reflux disease (GERD). (The area where esophageal mucosa is replaced by gastric mucosa is called Barretts esophagus, which carries the risk of developing into Barretts glandular cancer, a cancer that is more common in Europe and the United States.)
Esophageal regenerative therapy research has just started. Along with advancements in endoscopic and laparoscopic surgeries, this therapy is expected to advance further and become less invasive. In therapies involving substantial resections, some esophageal functions may be lost and trouble may occur due to the resection. By recovering such functions lost due to cancer, regenerative medicine can improve the post-operative QOL of patients and therefore we should continue to promote regenerative medical research.
Achievements
- Ohki T, Yamato M, Murakami D, Takagi R, Yang J, Namiki H, et al. Treatment of oesophageal ulcerations using endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in a canine model. Gut. 2006;55(12):1704 -10.
- Takagi R, Yamato M, Murakami D, Kondo M, Yang J, Ohki T, et al. Preparation of keratinocyte culture medium for the clinical applications of regenerative medicine. J Tissue Eng Regen Med. 2010;5(4):e63 -73.
- Takagi R, Murakami D, Kondo M, Ohki T, Sasaki R, Mizutani M, et al. Fabrication of human oral mucosal epithelial cell sheets for treatment of esophageal ulceration by endoscopic submucosal dissection. Gastrointest Endosc. 2010;72(6):1253 - 9.
