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

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.

Shattering barriers toward clinically meaningful MSC therapies

“…MSCs are generally distinct from other cell therapies as their therapeutic effect not only is dictated by cell-cell contact but also may include a so-called hit-and-run mechanism. Here, paracrine effectors from their secretome, including soluble cytokines, growth factors, hormones, and miRNA, are transferred to target cells such as immune cells and cells of damaged tissues through secretion, the uptake of biologics-loaded submicrometer extracellular vesicles (EVs), and immune-mediated phagocytosis ( 6 – 9 ), which can lead to long-term effects. In line with this, many studies have shown that secreted biologics and MSC-derived EVs containing biologically active molecules (such as proteins, lipids, and nucleic acids) retain the biological activity of parental MSCs and demonstrate a similar therapeutic effect in selected animal models ( 10 ).…”

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

“…Based on these attractive properties, MSC are recognized as tissue-repairing cells that may provide safe and effective cardiovascular cell therapies [5]. Moreover, accumulating evidence from in vivo and in vitro studies suggested that some of these reparative effects were mediated by paracrine factors secreted by MSC [6][7][8][9]. Recently, the biological factors in conditioned medium, including exosomes and soluble factors, derived from MSC have been extensively studied in different diseases, such as liver injury [10], glioma [11] and cardiovascular disease [12].…”

Ultra-fast self-gelling powder mediate robust wet adhesion to promote healing of gastrointestinal perforations

“…Enhanced healing of gastric perforation by PEI/PAA powder treatment. To further demonstrate that the PEI/PAA powder can be used as sealants to treat gastrointestinal perforation, we used an in-vivo rat gastric perforation model [42][43][44] (Fig. 5a).…”