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      Three-dimensional printed PLA scaffold and human gingival stem cell-derived extracellular vesicles: a new tool for bone defect repair

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          Abstract

          Background

          The role of bone tissue engineering in the field of regenerative medicine has been a main research topic over the past few years. There has been much interest in the use of three-dimensional (3D) engineered scaffolds (PLA) complexed with human gingival mesenchymal stem cells (hGMSCs) as a new therapeutic strategy to improve bone tissue regeneration. These devices can mimic a more favorable endogenous microenvironment for cells in vivo by providing 3D substrates which are able to support cell survival, proliferation and differentiation. The present study evaluated the in vitro and in vivo capability of bone defect regeneration of 3D PLA, hGMSCs, extracellular vesicles (EVs), or polyethyleneimine (PEI)-engineered EVs (PEI-EVs) in the following experimental groups: 3D-PLA, 3D-PLA + hGMSCs, 3D-PLA + EVs, 3D-PLA + EVs + hGMSCs, 3D-PLA + PEI-EVs, 3D-PLA + PEI-EVs + hGMSCs.

          Methods

          The structural parameters of the scaffold were evaluated using both scanning electron microscopy and nondestructive microcomputed tomography. Nanotopographic surface features were investigated by means of atomic force microscopy. Scaffolds showed a statistically significant mass loss along the 112-day evaluation.

          Results

          Our in vitro results revealed that both 3D-PLA + EVs + hGMSCs and 3D-PLA + PEI-EVs + hGMSCs showed no cytotoxicity. However, 3D-PLA + PEI-EVs + hGMSCs exhibited greater osteogenic inductivity as revealed by morphological evaluation and transcriptomic analysis performed by next-generation sequencing (NGS). In addition, in vivo results showed that 3D-PLA + PEI-EVs + hGMSCs and 3D-PLA + PEI-EVs scaffolds implanted in rats subjected to cortical calvaria bone tissue damage were able to improve bone healing by showing better osteogenic properties. These results were supported also by computed tomography evaluation that revealed the repair of bone calvaria damage.

          Conclusion

          The re-establishing of the integrity of the bone lesions could be a promising strategy in the treatment of accidental or surgery trauma, especially for cranial bones.

          Electronic supplementary material

          The online version of this article (10.1186/s13287-018-0850-0) contains supplementary material, which is available to authorized users.

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          Most cited references 48

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          Scaffolding in tissue engineering: general approaches and tissue-specific considerations.

          Scaffolds represent important components for tissue engineering. However, researchers often encounter an enormous variety of choices when selecting scaffolds for tissue engineering. This paper aims to review the functions of scaffolds and the major scaffolding approaches as important guidelines for selecting scaffolds and discuss the tissue-specific considerations for scaffolding, using intervertebral disc as an example.
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            Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo

            Emerging evidence suggests that extracellular vesicles (EVs) are secreted by diverse tissues and play important roles in cell-cell communication, organ interactions and tissue homeostasis. Studies have reported the use of EVs to stimulate tissue regeneration, such as hepatic cell regeneration, and to treat diseases, such as pulmonary hypertension. However, little is known about the osteogenic effect of EVs. In this study, we explore the role of bone marrow stromal cell-derived EVs in the regulation of osteoblast activity and bone regeneration. We isolated bone marrow stromal/stem cell (BMSC)-derived EVs through gradient ultracentrifugation and ultrafiltration, and tested the influence of the EVs on osteogenesis both in vivo and in vitro. The results indicated that EVs positively regulated osteogenic genes and osteoblastic differentiation but did not inhibit proliferation in vitro. Furthermore, we constructed an EVs delivery system to stimulate bone formation in Sprague Dawley (SD) rats with calvarial defects. We found that BMSC-derived EVs led to more bone formation in the critical-size calvarial bone defects. Moreover, we found that miR-196a plays an essential role in the regulation of osteoblastic differentiation and the expression of osteogenic genes. We anticipate that our assay using bone marrow stromal cell-derived EVs will become a valuable tool for promoting bone regeneration.
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              Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.

               Taisuke Furuta (corresponding) ,  Shigeru Miyaki,  Hiroyuki Ishitobi (2016)
              : Paracrine signaling by bone-marrow-derived mesenchymal stem cells (MSCs) plays a major role in tissue repair. Although the production of regulatory cytokines by MSC transplantation is a critical modulator of tissue regeneration, we focused on exosomes, which are extracellular vesicles that contain proteins and nucleic acids, as a novel additional modulator of cell-to-cell communication and tissue regeneration. To address this, we used radiologic imaging, histological examination, and immunohistochemical analysis to evaluate the role of exosomes isolated from MSC-conditioned medium (CM) in the healing process in a femur fracture model of CD9(-/-) mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9(-/-) mice was significantly lower than wild-type mice because of the retardation of callus formation. The retardation of fracture healing in CD9(-/-) mice was rescued by the injection of exosomes, but this was not the case after the injection of exosomes-free conditioned medium (CM-Exo). The levels of the bone repair-related cytokines, monocyte chemotactic protein-1 (MCP-1), MCP-3, and stromal cell-derived factor-1 in exosomes were low compared with levels in CM and CM-Exo, suggesting that bone repair may be in part mediated by other exosome components, such as microRNAs. These results suggest that exosomes in CM facilitate the acceleration of fracture healing, and we conclude that exosomes are a novel factor of MSC paracrine signaling with an important role in the tissue repair process.
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                Author and article information

                Contributors
                francesca.diomede@unich.it
                agnesegugli@hotmail.it
                paolo.cardelli@unich.it
                ilaria.merciaro@unich.it
                valeria.ettorre@unich.it
                t.traini@unich.it
                bedini.rossella@iss.it
                domenico.scionti@irccsme.it
                alessia.bramanti@irccsme.it
                antonio.nanci@umontreal.ca
                scaputi@unich.it
                antonella.fontana@unich.it
                emanuela.mazzon@irccsme.it
                +39.0871.355.4097 , trubiani@unich.it
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                13 April 2018
                13 April 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Department of Medical, Oral and Biotechnological Sciences, , University “G. d’Annunzio”, ; Chieti, Italy
                [2 ]GRID grid.419419.0, IRCCS Centro Neurolesi “Bonino Pulejo”, ; Messina, Italy
                [3 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Department of Pharmacy, , University “G. d’Annunzio”, ; Chieti, Italy
                [4 ]ISNI 0000 0000 9120 6856, GRID grid.416651.1, National Centre of Innovative Technologies in Public Health, Italian National Institute of Health, ; Rome, Italy
                [5 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Institute of Applied Science and Intelligent Systems “ISASI Eduardo Caianiello”, CNR, ; Messina, Italy
                [6 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Laboratory for the study of Calcified Tissues and Biomaterials, Department of Stomatology, Faculty of Dentistry, , Université de Montréal, ; Montréal, Québec, Canada
                [7 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Department of Medical, Oral and Biotechnological Sciences, , University “G. d’Annunzio”, ; Via dei Vestini, 66100 Chieti, Italy
                Article
                850
                10.1186/s13287-018-0850-0
                5899396
                29653587
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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