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      Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration

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          Abstract

          A novel strategy to deliver therapeutic exosomes to bone is developed for the first time by conjugating a specific BMSC-targeting aptamer to the exosomal surface.

          Abstract

          In elderly people particularly in postmenopausal women, inadequate bone formation by osteoblasts originating from bone marrow mesenchymal stem cells (BMSCs) for compensation of bone resorption by osteoclasts is a major reason for osteoporosis. Enhancing osteoblastic differentiation of BMSCs is a feasible therapeutic strategy for osteoporosis. Here, bone marrow stromal cell (ST)-derived exosomes (STExos) are found to remarkably enhance osteoblastic differentiation of BMSCs in vitro. However, intravenous injection of STExos is inefficient in ameliorating osteoporotic phenotypes in an ovariectomy (OVX)-induced postmenopausal osteoporosis mouse model, which may be because STExos are predominantly accumulated in the liver and lungs, but not in bone. Hereby, the STExo surface is conjugated with a BMSC-specific aptamer, which delivers STExos into BMSCs within bone marrow. Intravenous injection of the STExo-Aptamer complex enhances bone mass in OVX mice and accelerates bone healing in a femur fracture mouse model. These results demonstrate the efficiency of BMSC-specific aptamer-functionalized STExos in targeting bone to promote bone regeneration, providing a novel promising approach for the treatment of osteoporosis and fracture.

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          Most cited references 45

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          Is Open Access

          Extracellular vesicles: Exosomes, microvesicles, and friends

          Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.
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            Aptamers as targeted therapeutics: current potential and challenges

            Nucleic acid aptamers offer several advantages over traditional antibodies, but their clinical translation has been delayed by several factors, including insufficient potency, lack of safety data and high production costs. Here, Zhou and Rossi provide an overview of aptamer generation, focusing on recent technological advances and clinical development, as well as challenges and lessons learned.
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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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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                NANOHL
                Nanoscale
                Nanoscale
                Royal Society of Chemistry (RSC)
                2040-3364
                2040-3372
                November 7 2019
                2019
                : 11
                : 43
                : 20884-20892
                Affiliations
                [1 ]Department of Orthopedics
                [2 ]Xiangya Hospital
                [3 ]Central South University
                [4 ]Changsha
                [5 ]China
                [6 ]The Second Xiangya Hospital
                [7 ]Movement System Injury and Repair Research Center
                [8 ]Xiangya Nursing School
                Article
                10.1039/C9NR02791B
                © 2019
                Product
                Self URI (article page): http://xlink.rsc.org/?DOI=C9NR02791B

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