Dataset Information

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.

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.

SUBMITTER: Furuta T

PROVIDER: S-EPMC5189643 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.

Furuta Taisuke T Miyaki Shigeru S Ishitobi Hiroyuki H Ogura Toshihiko T Kato Yoshio Y Kamei Naosuke N Miyado Kenji K Higashi Yukihito Y Ochi Mitsuo M

Stem cells translational medicine 20160726 12

: 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 immunohis ...[more]

PMID: 27460850

Similar Datasets

Project description:BackgroundAt present, bone union delay or failure remains challenging for clinicians. It has been reported that adipose-derived mesenchymal stem cells (ADMSCs) offer a promising way to promote bone fracture healing. In recent years, nanomaterials have been applied in regenerative medicine. This study aimed to investigate whether ADMSCs combined with platinum nanoparticles (PtNPs) could further improve fracture healing on the basis of ADMSCs.MethodsADMSCs were co-cultured with PtNPs in vitro to investigate the effect of PtNPs on the differentiation of ADMSCs. Twenty Sprague-Dawley (SD) rats were randomly divided into four groups (with five rats in each group). The left tibias of all rats were fractured. Phosphate-buffered saline (PBS), PtNPs, ADMSC, and ADMSC mixed with PtNPs were then injected into the fracture sites based on the group classifications. The fracture was monitored by X-ray immediately after the fracture and on days 14 and 28 post-fracture. The tibias of the rats were subsequently harvested after the last X-ray and evaluated by micro computed tomography (micro-CT), histological analysis, and immunohistochemical detection.ResultsPtNPs significantly enhanced the osteogenic differentiation of ADMSCs in vitro. On days 14 and 28 post-fracture, the radiographic score of the ADMSC + PtNPs group was higher than that of the ADMSC group, the score of the ADMSC group was higher than that of the PtNPs and control groups, and there was no significant difference between the PtNPs and control groups. Micro-CT confirmed that combined ADMSCs with PtNPs were more effective than using ADMSCs alone in promoting fracture healing. The histological and immunohistochemical results further supported this conclusion.ConclusionsOur findings demonstrated that PtNPs could promote osteogenic differentiation of ADMSC in vitro. ADMSCs combined with PtNPs could accelerate fracture healing further in vivo and are a promising a potential method for the treatment of fracture healing.

Project description:PurposeHuman corneal endothelial cells (hCECs) have been considered unable to regenerate in vivo, resulting in corneal decompensation after significant loss of hCECs. adipose-derived mesenchymal stem cell (ASC)-derived exosomes can regenerate tissues and organs. In this study, we investigated whether ASC-derived exosomes could protect and regenerate CECs.MethodsWe performed cell viability and cell-cycle analyses to evaluate the effect of ASC-derived exosomes on the regeneration capacity of cultured hCECs. Transforming growth factor-β (TGF-β) and hydrogen peroxide (H2O2) were used to induce biological stress in CECs. The effect of ASC-derived exosomes on CECs was investigated in vivo. ASC-derived exosomes were introduced into rat CECs using electroporation, and rat corneas were injured using cryoinjury. Next-generation sequencing analysis was performed to compare the differentially expressed microRNAs (miRNAs) between ASC-derived and hCEC-derived exosomes.ResultsASC-derived exosomes induced CEC proliferation and suppressed TGF-β- or H2O2-induced oxidative stress and senescence. ASC-derived exosomes protect hCECs against TGF-β- or H2O2-induced endothelial-mesenchymal transition and mitophagy. In an in vivo study, ASC-derived exosomes promoted wound healing of rat CECs and protected the corneal endothelium against cryoinjury-induced corneal endothelium damage. Next-generation sequencing analysis revealed differentially expressed miRNAs for ASC-derived and hCEC-derived exosomes. They are involved in lysine degradation, adherens junction, the TGF-β signaling pathway, the p53 signaling pathway, the Hippo signaling pathway, the forkhead box O (FoxO) signaling pathway, regulation of actin cytoskeleton, and RNA degradation based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.ConclusionsASC-derived exosomes promoted wound healing and regeneration of endothelial cells by inducing a shift in the cell cycle and suppressing senescence and autophagy.

Project description:Graft healing after anterior cruciate ligament reconstruction (ACLR) involves slow biological processes, and various types of biological modulations have been explored to promote tendon-to-bone integration. Exosomes have been extensively studied as a promising new cell-free strategy for tissue regeneration, but few studies have reported their potential in tendon-to-bone healing. In this study, a novel type of exosome derived from magnetically actuated (iron oxide nanoparticles (IONPs) combined with a magnetic field) bone mesenchymal stem cells (BMSCs) (IONP-Exos) was developed, and the primary purpose of this study was to determine whether IONP-Exos exert more significant effects on tendon-to-bone healing than normal BMSC-derived exosomes (BMSC-Exos). Here, we isolated and characterized the two types of exosomes, conducted in vitro experiments to measure their effects on fibroblasts (NIH3T3), and performed in vivo experiments to compare the effects on tendon-to-bone integration. Moreover, functional exploration of exosomal miRNAs was further performed by utilizing a series of gain- and loss-of-function experiments. Experimental results showed that both BMSC-Exos and IONP-Exos could be shuttled intercellularly into NIH3T3 fibroblasts and enhanced fibroblast activity, including proliferation, migration, and fibrogenesis. In vivo, we found that IONP-Exos significantly prevented peri-tunnel bone loss, promoted more osseous ingrowth into the tendon graft, increased fibrocartilage formation at the tendon-bone tunnel interface, and induced a higher maximum load to failure than BMSC-Exos. Furthermore, overexpression of miR-21-5p remarkably enhanced fibrogenesis in vitro, and SMAD7 was shown to be involved in the promotive effect of IONP-Exos on tendon-to-bone healing. Our findings may provide new insights into the regulatory roles of IONPs in IONP-Exos communication via stimulating exosomal miR-21-5p secretion and the SMAD7 signaling pathway in the fibrogenic process of tendon-to-bone integration. This work could provide a new strategy to promote tendon-to-bone healing for tissue engineering in the future.

Dataset Information

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.

Significance

Publications

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets