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

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          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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          Most cited references42

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          Stem cell transplantation: the lung barrier.

          Mesenchymal stem cells (MSCs) show differentiation capacity along mesenchymal lineages and have the potential to aid tissue regeneration. MSC transplantation strategies are therefore currently being assessed following injury to various organs. However, potential MSC migration to these organs after intravenous (IV) MSC injection continues to be impeded by cell trapping within the lung. Mouse MSCs were isolated, purified, transfected with firefly luciferase, and labeled with CSFE. Their size was assessed in vitro. To estimate the diameter of mouse pulmonary capillaries, fluorescence-labeled microspheres of different sizes were injected with or without sodium nitroprusside (SN) pretreatment. The lungs were harvested after 30 seconds and mean numbers of trapped microspheres per high-power field (HPF) were calculated. After IV injection of MSC suspensions (with or without SN), their dynamic distribution was monitored by in vivo luciferine imaging as well as by histopathology. The diameter of suspended MSCs in vitro was 15 to 19 microm. Whereas nearly no 4-microm microspheres could be detected in lung sections, the numbers of trapped 10- and 15-microm microspheres could be significantly decreased by prior SN injection from 19.3 +/- 11.1 to 6.0 +/- 1.6 cells/HPF (P = .004) and from 34.9 +/- 11.9 to 25.6 +/- 8.1 cells/HPF (P = .028), respectively. Within seconds after MSC IV injection, the vast majority of cells was found in the lungs. However, cell trapping in the pulmonary microvasculature was significantly reduced by pre-treatment with SN. We demonstrate that cell trapping in lungs can be reduced with IV SN pretreatment, increasing MSC passage through the lung capillaries, and potentially facilitating cell access to injured organs.
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            The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration.

            The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications.
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              Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis

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                Author and article information

                Journal
                Science Translational Medicine
                Sci. Transl. Med.
                American Association for the Advancement of Science (AAAS)
                1946-6234
                1946-6242
                October 30 2019
                October 30 2019
                October 30 2019
                October 30 2019
                : 11
                : 516
                : eaat7455
                Affiliations
                [1 ]Department of Surgery and State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, People’s Republic of China.
                [2 ]Chow Yuk Ho Technology Center for Innovative Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, People’s Republic of China.
                [3 ]Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong SAR 999077, People’s Republic of China.
                [4 ]Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Anhui Province 230001, People’s Republic of China.
                Article
                10.1126/scitranslmed.aat7455
                31666403
                9c552714-ad78-4d17-a306-d7dfe46976f5
                © 2019

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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