Research ArticleRegenerative Medicine

Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs

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Science Translational Medicine  30 Oct 2019:
Vol. 11, Issue 516, eaat7455
DOI: 10.1126/scitranslmed.aat7455

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Secreting healing factors

One of the main adverse events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the development of gastric ulcers. Proton pump inhibitors are used to alleviate this adverse event; however, they are associated with serious adverse events. Now, Xia et al. developed a porcine model of NSAID-induced gastric ulcers and showed that intragastric administration of adipose tissue–derived mesenchymal stem cells (ADMSCs) rapidly promoted healing and reduced gastric inflammation. The therapeutic effect was mediated by activation of the ErK and Akt pathways in ulcer tissue induced by stem cell–secreted factors. The results suggest that mesenchymal stem cells or their secretome could be effective in treating NSAID-induced gastric ulcers.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal–regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.

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