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Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.
Stem Cells Transl Med 2016; 5(12):1620-1630SC

Abstract

: 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.

Authors+Show Affiliations

Department of Orthopaedics Surgery, Integrated Health Sciences, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan fu09100913@yahoo.co.jp.Department of Orthopaedics Surgery, Integrated Health Sciences, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. Department of Regenerative Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.Department of Regenerative Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.Department of Orthopaedics Surgery, Integrated Health Sciences, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. Department of Regenerative Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.Department of Reproductive Biology, National Center for Child Health and Development, Tokyo, Japan.Department of Regenerative Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.Department of Orthopaedics Surgery, Integrated Health Sciences, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27460850

Citation

Furuta, Taisuke, et al. "Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model." Stem Cells Translational Medicine, vol. 5, no. 12, 2016, pp. 1620-1630.
Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. Stem Cells Transl Med. 2016;5(12):1620-1630.
Furuta, T., Miyaki, S., Ishitobi, H., Ogura, T., Kato, Y., Kamei, N., ... Ochi, M. (2016). Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. Stem Cells Translational Medicine, 5(12), pp. 1620-1630.
Furuta T, et al. Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. Stem Cells Transl Med. 2016;5(12):1620-1630. PubMed PMID: 27460850.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. AU - Furuta,Taisuke, AU - Miyaki,Shigeru, AU - Ishitobi,Hiroyuki, AU - Ogura,Toshihiko, AU - Kato,Yoshio, AU - Kamei,Naosuke, AU - Miyado,Kenji, AU - Higashi,Yukihito, AU - Ochi,Mitsuo, Y1 - 2016/07/26/ PY - 2015/11/02/received PY - 2016/06/28/accepted PY - 2016/7/28/pubmed PY - 2017/6/2/medline PY - 2016/7/28/entrez KW - Cytokine KW - Endochondral ossification KW - Exosomes KW - Fracture healing KW - Mesenchymal stem cells KW - microRNA SP - 1620 EP - 1630 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 5 IS - 12 N2 - : : 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. SN - 2157-6564 UR - https://www.unboundmedicine.com/medline/citation/27460850/Mesenchymal_Stem_Cell_Derived_Exosomes_Promote_Fracture_Healing_in_a_Mouse_Model_ L2 - https://doi.org/10.5966/sctm.2015-0285 DB - PRIME DP - Unbound Medicine ER -