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      M2 Macrophagy-derived exosomal miRNA-5106 induces bone mesenchymal stem cells towards osteoblastic fate by targeting salt-inducible kinase 2 and 3

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          Abstract

          Background

          Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo, and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation.

          Results

          We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 ( SIK2 and SIK3) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo.

          Conclusions

          Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

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          Most cited references27

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          Fracture healing under healthy and inflammatory conditions.

          Optimal fracture treatment requires knowledge of the complex physiological process of bone healing. The course of bone healing is mainly influenced by fracture fixation stability (biomechanics) and the blood supply to the healing site (revascularization after trauma). The repair process proceeds via a characteristic sequence of events, described as the inflammatory, repair and remodeling phases. An inflammatory reaction involving immune cells and molecular factors is activated immediately in response to tissue damage and is thought to initiate the repair cascade. Immune cells also have a major role in the repair phase, exhibiting important crosstalk with bone cells. After bony bridging of the fragments, a slow remodeling process eventually leads to the reconstitution of the original bone structure. Systemic inflammation, as observed in patients with rheumatoid arthritis, diabetes mellitus, multiple trauma or sepsis, can increase fracture healing time and the rate of complications, including non-unions. In addition, evidence suggests that insufficient biomechanical conditions within the fracture zone can influence early local inflammation and impair bone healing. In this Review, we discuss the main factors that influence fracture healing, with particular emphasis on the role of inflammation.
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            MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation.

            Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra-bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss.
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              Understanding the role of immune regulation in wound healing.

              The immune system plays an integral role in successful wound healing. In addition to contributing to host defenses and inflammation, immune cells are critical regulators of wound healing through the secretion of cytokines, lymphokines, and growth factors. We review the mechanisms by which the immune system regulates wound healing.
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                Author and article information

                Contributors
                mibobin@hust.edu.cn
                liuguohui@hust.edu.cn
                Journal
                J Nanobiotechnology
                J Nanobiotechnology
                Journal of Nanobiotechnology
                BioMed Central (London )
                1477-3155
                28 April 2020
                28 April 2020
                2020
                : 18
                : 66
                Affiliations
                [1 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Orthopaedics, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430022 China
                [2 ]GRID grid.24516.34, ISNI 0000000123704535, Department of Orthopedic Surgery, Tongji Hospital, , Tongji University School of Medicine, ; Shanghai, 200065 China
                [3 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Neurosurgery, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430022 China
                Author information
                http://orcid.org/0000-0002-2013-1396
                Article
                622
                10.1186/s12951-020-00622-5
                7189726
                32345321
                dc92fa0f-543c-4275-91eb-67cb9c4dd8f2
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 18 March 2020
                : 21 April 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81772345
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004572, National Health and Family Planning Commission of the People's Republic of China;
                Award ID: No. ZX-01-018
                Award ID: ZX-01-C2106153
                Award Recipient :
                Funded by: Ministry of Science and Technology of the People’s Republic of   China
                Award ID: 2018YFC2001502
                Award ID: 2018YFB1105705
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Biotechnology
                exosome,mir-5106,osteoblast,fracture,sik2,sik3
                Biotechnology
                exosome, mir-5106, osteoblast, fracture, sik2, sik3

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