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      Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases

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          Abstract

          Mesenchymal stem/stromal cells (MSCs) represent a promising therapy for musculoskeletal diseases. There is compelling evidence indicating that MSC effects are mainly mediated by paracrine mechanisms and in particular by the secretion of extracellular vesicles (EVs). Many studies have thus suggested that EVs may be an alternative to cell therapy with MSCs in tissue repair. In this review, we summarize the current understanding of MSC EVs actions in preclinical studies of (1) immune regulation and rheumatoid arthritis, (2) bone repair and bone diseases, (3) cartilage repair and osteoarthritis, (4) intervertebral disk degeneration and (5) skeletal muscle and tendon repair. We also discuss the mechanisms underlying these actions and the perspectives of MSC EVs-based strategies for future treatments of musculoskeletal disorders.

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          Role of cytokines in intervertebral disc degeneration: pain and disc content.

          Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.
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            Cellular internalization of exosomes occurs through phagocytosis.

            Exosomes play important roles in many physiological and pathological processes. However, the exosome-cell interaction mode and the intracellular trafficking pathway of exosomes in their recipient cells remain unclear. Here, we report that exosomes derived from K562 or MT4 cells are internalized more efficiently by phagocytes than by non-phagocytic cells. Most exosomes were observed attached to the plasma membrane of non-phagocytic cells, while in phagocytic cells these exosomes were found to enter via phagocytosis. Specifically, they moved to phagosomes together with phagocytic polystyrene carboxylate-modified latex beads (biospheres) and were further sorted into phagolysosomes. Moreover, exosome internalization was dependent on the actin cytoskeleton and phosphatidylinositol 3-kinase, and could be inhibited by the knockdown of dynamin2 or overexpression of a dominant-negative form of dynamin2. Further, antibody pretreatment assays demonstrated that tim4 but not tim1 was involved in exosomes uptake. We also found that exosomes did not enter the internalization pathway involving caveolae, macropinocytosis and clathrin-coated vesicles. Our observation that the cellular uptake of exosomes occurs through phagocytosis has important implications for exosome-cell interactions and the exosome intracellular trafficking pathway.
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              Periodontitis: facts, fallacies and the future.

              This volume of Periodontology 2000 represents the 25th anniversary of the Journal, and uses the occasion to assess important advancements in periodontology over the past quarter-century as well as the hurdles that remain. Periodontitis is defined by pathologic loss of the periodontal ligament and alveolar bone. The disease involves complex dynamic interactions among active herpesviruses, specific bacterial pathogens and destructive immune responses. Periodontal diagnostics is currently based on clinical rather than etiologic criteria, and provides limited therapeutic guidance. Periodontal causative treatment consists of scaling, antiseptic rinses and occasionally systemic antibiotics, and surgical intervention has been de-emphasized, except perhaps for the most advanced types of periodontitis. Plastic surgical therapy includes soft-tissue grafting to cover exposed root surfaces and bone grafting to provide support for implants. Dental implants are used to replace severely diseased or missing teeth, but implant overuse is of concern. The utility of laser treatment for periodontitis remains unresolved. Host modulation and risk-factor modification therapies may benefit select patient groups. Patient self-care is a critical part of periodontal health care, and twice-weekly oral rinsing with 0.10-0.25% sodium hypochlorite constitutes a valuable adjunct to conventional anti-plaque and anti-gingivitis treatments. A link between periodontal herpesviruses and systemic diseases is a strong biological plausibility. In summary, research during the past 25 years has significantly changed our concepts of periodontitis pathobiology and has produced more-effective and less-costly therapeutic options.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                31 December 2019
                January 2020
                : 9
                : 1
                : 98
                Affiliations
                [1 ]Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain
                [2 ]Department of Pharmacy, Cardenal Herrera-CEU University, Ed. Ciencias de la Salud, 46115 Alfara, Valencia, Spain
                Author notes
                [* ]Correspondence: maria.j.alcaraz@ 123456uv.es
                Author information
                https://orcid.org/0000-0002-5459-6407
                https://orcid.org/0000-0002-4369-9849
                Article
                cells-09-00098
                10.3390/cells9010098
                7017209
                31906087
                ebd32f28-c054-4d81-b8cd-4aef63bb6706
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 November 2019
                : 28 December 2019
                Categories
                Review

                mesenchymal stem cells,extracellular vesicles,immunoregulation,bone diseases,osteoarthritis

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