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Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model
Open accessAbstract
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. Significance: This work focuses on exosomes, which are extracellular vesicles, as a novel additional modulator of cell-to-cell communication. This study evaluated the role of exosomes isolated from mesenchymal stem cell (MSC)-conditioned medium (MSC-CM) in the fracture-healing process of CD9−/− mice, a strain that is known to produce reduced levels of exosomes. Retardation of fracture healing in CD9−/− mice was rescued by the injection of MSC exosomes, but this was not the case after the injection of exosome-free CM. This study finds that MSC exosomes are a novel factor of MSC paracrine signaling, with an important role in the tissue repair process.
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“Administration of MSCs derived exosomes has been reported to be efficacious in promoting skeletal muscle regeneration [12], cartilage repair [13], and bone fracture healing [14], and cutaneous wound healing [15].”
From A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties (2022) · cites this paper as [14]
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Metadata
- Authors
- Furuta, T., Miyaki, S., Ishitobi, H., Ogura, T., Kato, Y., Kamei, N., Miyado, K., Higashi, Y., & Ochi, M.
- Affiliations
- Hiroshima University (JP)
- Hiroshima University Hospital (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- National Center For Child Health and Development (JP)
- Corresponding author
- Furuta, Taisuke
- ORCID
- Venue
- Stem Cells Translational Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-07-26
- Volume
- 5
- Issue
- 12
- Pages
- 1620-1630
- ISSN
- 2157-6564 (ISSN-L)
- 2157-6580
- PMC
- PMC5189643
- OpenAlex
- W2490529699
- Cited by
- 444
- References
- 60
- Citations by year
- 2026: 18 · 2025: 35 · 2024: 41 · 2023: 44 · 2022: 52 · 2021: 90 · 2020: 64 · 2019: 44 · 2018: 37 · 2017: 17 · 2016: 1
- FWCI
- 17.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells Translational Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Hiroshima University Acedemic Information Repository (Hiroshima University) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (21249079)
- Japan Society for the Promotion of Science (26293363, 16K21192, 15H04959, 24689057, 14J05729, 21249079, 15H04365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone fractures and treatments
- Keywords
- mesenchymal stem cells, exosomes, fracture healing, paracrine signaling, extracellular vesicles, CD9, conditioned medium, callus formation, bone regeneration, microRNA, CXCL12, MCP-1, tissue regeneration
- MeSH terms
- Animals, Body Weight, Disease Models, Animal, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Tibia, Bone Density, Cytokines, Culture Media, Conditioned, Fracture Healing, Gene Expression Profiling, MicroRNAs, Cell Line, Tumor, Exosomes, Mesenchymal Stem Cells, Tetraspanin 29
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