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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

      105,621 Monthly downloads/views I 7.033 Impact Factor I 10.9 CiteScore I 1.22 Source Normalized Impact per Paper (SNIP) I 1.032 Scimago Journal & Country Rank (SJR)

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      A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells

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          Abstract

          Purpose

          The combination of oral derived stem cells and 3-D scaffolds is considered advantageous in bone repair. In particular, collagen membranes possess ideal biological properties and can support infiltration and proliferation of osteoblasts, promoting bone regeneration. Our study aimed to develop a new biocompatible osteogenic construct composed of a commercially available collagen membrane (Evolution [Evo]), human periodontal-ligament stem cells (hPDLSCs) enriched with extracellular vesicles (EVs), or polyethylenimine (PEI)-engineered EVs (PEI-EVs).

          Methods

          Osteogenic ability and expression of osteogenic genes were evaluated in vitro in hPDLSCs cultured with or without Evo, with Evo and EVs, or PEI-EVs. In addition, the bone-regeneration capacity of Evo, Evo enriched with hPDLSCs, Evo enriched with hPDLSCs and EVs/PEI-EVs was investigated in rats subjected to calvarial defects.

          Results

          Our results showed that Evo enriched with EVs and PEI-EVs showed high biocompatibility and osteogenic properties in vitro and in vivo. In addition, quantitative reverse-transcription polymerase chain reaction demonstrated the upregulation of osteogenic genes, such as TGFB1, MMP8, TUFT1, TFIP11, BMP2, and BMP4, in the presence of PEI-EVs. Upregulation of BMP2/4 was confirmed for Evo enriched with PEI-EVs and hPDLSCs both in vitro by Western blot and in vivo by immunofluorescence.

          Conclusion

          Our results indicated that Evo enriched with hPDLSCs and PEI-EVs is able to promote a bone-regeneration process for the treatment of calvarium and ossification defects caused by accidental or surgery trauma. In particular, PEI-EVs had a significant role in activation of the osteogenic process.

          Most cited references43

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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

          Yunhao Qin, Lian Wang, Zhengliang Gao … (2016)
          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, 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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              Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway

              Jieyuan Zhang, Xiaolin Liu, Haiyan Li … (2016)
              Background Recently, accumulating evidence has shown that exosomes, the naturally secreted nanocarriers of cells, can exert therapeutic effects in various disease models in the absence of parent cells. However, application of exosomes in bone defect repair and regeneration has been rarely reported, and little is known regarding their underlying mechanisms. Methods Exosomes derived from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos) were combined with tricalcium phosphate (β-TCP) to repair critical-sized calvarial bone defects, and the efficacy was assessed by histological examination. We evaluated the in vitro effects of hiPSC-MSC-Exos on the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) by cell-counting, scratch assays, and qRT-PCR, respectively. Gene expression profiling and bioinformatics analyses were also used to identify the underlying mechanisms in the repair. Results We found that the exosome/β-TCP combination scaffolds could enhance osteogenesis as compared to pure β-TCP scaffolds. In vitro assays showed that the exosomes could release from β-TCP and could be internalized by hBMSCs. In addition, the internalization of exosomes into hBMSCs could profoundly enhance the proliferation, migration, and osteogenic differentiation of hBMSCs. Furthermore, gene expression profiling and bioinformatics analyses demonstrated that exosome/β-TCP combination scaffolds significantly altered the expression of a network of genes involved in the PI3K/Akt signaling pathway. Functional studies further confirmed that the PI3K/Akt signaling pathway was the critical mediator during the exosome-induced osteogenic responses of hBMSCs. Conclusions We propose that the exosomes can enhance the osteoinductivity of β-TCP through activating the PI3K/Akt signaling pathway of hBMSCs, which means that the exosome/β-TCP combination scaffolds possess better osteogenesis activity than pure β-TCP scaffolds. These results indicate that naturally secreted nanocarriers-exosomes can be used as a bioactive material to improve the bioactivity of the biomaterials, and that hiPS-MSC-Exos combined with β-TCP scaffolds can be potentially used for repairing bone defects. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0391-3) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nanomedicine
                Journal ID (iso-abbrev): Int J Nanomedicine
                Journal ID (publisher-id): International Journal of Nanomedicine
                Title: International Journal of Nanomedicine
                Publisher: Dove Medical Press
                ISSN (Print): 1176-9114
                ISSN (Electronic): 1178-2013
                Publication date Collection: 2018
                Publication date (Electronic): 29 June 2018
                Volume: 13
                Pages: 3805-3825
                Affiliations
                [1 ]Department of Medical, Oral, and Biotechnological Sciences, University “G. d’Annunzio”, Chieti, Italy
                [2 ]Department of Psychological, Health, and Territorial Sciences, University “G. d’Annunzio”, Chieti, Italy
                [3 ]Department of Experimental Neurology, IRCCS Centro Neurolesi “Bonino Pulejo”, Messina, Italy, emazzon.irccs@ 123456gmail.com
                [4 ]Department of Pharmacy, University “G. d’Annunzio”, Chieti, Italy
                [5 ]Eduardo Caianiello Institute of Applied Science and Intelligent Systems (ISASI), National Research Council, Messina, Italy
                Author notes
                Correspondence: Emanuela Mazzon, IRCCS Centro Neurolesi “Bonino Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina ME, Italy, Tel +39 90 6012 8172, Fax +39 90 6012 8108, Email emazzon.irccs@ 123456gmail.com
                Article
                Publisher ID: ijn-13-3805
                DOI: 10.2147/IJN.S162836
                PMC ID: 6029600
                PubMed ID: 29988728
                SO-VID: 5d11ff70-b58d-479a-9d73-0d076fd08e45
                Copyright © © 2018 Diomede et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Molecular medicine
                Keywords: human periodontal-ligament stem cells,living construct,extracellular vesicles,bone regeneration,collagen membrane
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: human periodontal-ligament stem cells, living construct, extracellular vesicles, bone regeneration, collagen membrane

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