IDDF2018-ABS-0194 Adipose-derived mesenchymal stem cells promote healing of nsaid-related gastric ulcer through the paracrine effects in pigs

Abstract

Background Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) will induce severe gastrointestinal toxicity. Stem cell therapy is proposed to facilitate tissue repair and regeneration. This study aimed to investigate whether endoscopic submucosal injection of adipose-derived mesenchymal stem cells (ADMSCs) could accelerate healing of NSAID-related gastric ulcer. Methods Porcine model of NSAID-related gastric ulcer was induced by indomethacin and endoscopic submucosal dissection (ESD)(Fig 1A). Indomethacin was given in all porcine models 10 days prior to ESD. We performed ESD at body and antrum of the stomach in each pig under general anaesthesia to create the ulcer model. After ESD, one of the ulcers was treated by endoscopic submucosal injection of ADMSCs, while the other ulcer was injected with saline as control. Further endoscopic injections were performed at respective ulcer on day 7 and 14. Indomethacin was continued after ESD until pigs were euthanized on day 21. Endoscopic surveillance was performed every week to measure the ulcer healing. Results ADMSCs delivered by the endoscopic submucosal injection led to more efficient healing of NSAID-related gastric ulcer, with a significant wound closure observed by day 7 compared with the control (IDDF2018-ABS-0194 Figure 1. B, C). Ulcers in the ADMSCs group displayed enhanced re-epithelization and angiogenesis, and reduced inflammation on day 7 and 21 (IDDF2018-ABS-0194 Figure 1. D-G). Moreover, few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the stem cell-assisted ulcer healing may not rely on cell differentiation (IDDF2018-ABS-0194 Figure 1. H, I). A further experiment with submucosal injection of MSC-derived secretome revealed that the therapeutic efficacy of NSAID-related gastric ulcer was comparable to stem cell transplantation (IDDF2018-ABS-0194 Figure 2. A, B). Profiling analysis showed significant up-regulation of genes associated with inflammation, granulation and extracellular matrix remodelling (IDDF2018-ABS-0194 Figure 2. C, D). In addition, the ErK1/2-MAPK pathway was activated by injection of ADMSCs or MSC-derived secretome (IDDF2018-ABS-0194 Figure 2. E, F). Conclusions Our results showed that endoscopic submucosal injection of ADMSCs served as a novel approach to promote healing of NSAID-related gastric ulcer, while the paracrine activity of stem cell played a more important role in this process (IDDF2018-ABS-0194 Figure 2. G).