Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs.
OBJECTIVE
Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD.


METHODS
We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis.


RESULTS
Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8.


CONCLUSIONS
CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Takeshi
T
Mizushima
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shunsuke
S
Ohnishi
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hidetaka
H
Hosono
Department of Transfusion Medicine and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Japan.
Kenichi
K
Yamahara
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Momoko
M
Tsuda
Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan.
Yuichi
Y
Shimizu
Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan.
Mototsugu
M
Kato
Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Masahiro
M
Asaka
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Naoya
N
Sakamoto
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D000069916:Endoscopic Mucosal Resection / Q000009:adverse effects*; D004940:Esophageal Stenosis / Q000209:etiology / Q000517:prevention & control*; D004945:Esophagoscopy; D004947:Esophagus / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D059630:Mesenchymal Stem Cells; D058628:Myofibroblasts / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D034421:Sus scrofa; D013552:Swine; D014222:Triamcinolone Acetonide / Q000494:pharmacology
D017077:Culture Media, Conditioned; D005938:Glucocorticoids; D014222:Triamcinolone Acetonide