Mesenchymal‐stem‐cell‐derived exosomes accelerate skeletal muscle regeneration

Nakamura, Yoshihiro; Miyaki, Shigeru; Ishitobi, Hiroyuki; Matsuyama, Sho; Nakasa, Tomoyuki; Kamei, Naosuke; Akimoto, Takayuki; Higashi, Yukihito; Ochi, Mitsuo

doi:10.1016/j.febslet.2015.03.031

Cited by 443 publications

(367 citation statements)

References 31 publications

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“…CM contains high levels of angiogenic factors such as VEGF and IL-6 and enhances bone ingrowth and fracture healing by stimulating endothelial cells [47]. However, as we previously reported, although VEGF and IL-6 levels in MSC exosomes are low compared with CM and CM-Exo, MSC exosomes induce angiogenesis to a greater extent [36]. These results suggest that the acceleration of fracture healing by MSC exosomes is not solely attributable to MCP-1, -3, SDF-1, and angiogenic factors.…”

Section: /2mentioning

confidence: 68%

“…system. We previously described the top 20 most highly expressed miRNAs in MSC exosomes and CM-Exo [36]. The top 30 most highly expressed miRNAs in MSC and HOS exosomes were very similar (Table 1).…”

Section: Cytokines and Micrornas In Msc Exosomesmentioning

confidence: 71%

“…Purified small RNAs were concentrated by using an evaporator. The concentrations and quality of the small RNAs from the same volumes of culture medium for the same numbers of cells were determined with the BioAnalyzer 2100 (Agilent Technologies, Santa Clara, CA, http:// www.agilent.com), and small RNA was used as the input for the nCounter Human miRNA Expression Assay Kit (NanoString Technologies, Seattle, WA, http://www.nanostring.com) as described previously [36].…”

Section: Nanostring Ncounter Microrna Analysismentioning

confidence: 99%

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

Furuta

Miyaki

Ishitobi

et al. 2016

Stem Cells Translational Medicine

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371

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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 2/2 mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9 2/2 mice was significantly lower than wild-type mice because of the retardation of callus formation. The retardation of fracture healing in CD9 2/2 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 repairrelated 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. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1620-1630 SIGNIFICANCEThis 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 2/2 mice, a strain that is known to produce reduced levels of exosomes. Retardation of fracture healing in CD9 2/2 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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Section: /2mentioning

confidence: 68%

Section: Cytokines and Micrornas In Msc Exosomesmentioning

confidence: 71%

Section: Nanostring Ncounter Microrna Analysismentioning

confidence: 99%

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

Furuta

Miyaki

Ishitobi

et al. 2016

Stem Cells Translational Medicine

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371

362

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“…In the cardiovascular system, exosomes have been suggested as cardioprotective agents (Lai et al, 2010); they have been shown to have proangiogenic effects (Bian et al, 2014) and involvement in reduction of apoptosis and cardiac fibrosis (Feng et al, 2014). Arslan et al (2013) showed that a single intravenous administration of exosomes was effective in enhancing cardiac function and geometry after myocardial infarction due to bioenergetics re-establishment (increased ATP production), oxidative stress reduction and prosurvival signaling activation (enhanced PI3K/Akt signaling) (Arslan et al, 2013 (Nakamura et al, 2015). In the nervous system, MSC derived exosomes have been evaluated in the treatment of neurological and neurodegenerative diseases; they have been shown to enhance angiogenesis and neurogenesis, reduce inflammation and improve spatial learning and sensorimotor function (Kim et al, 2016;Zhang et al, 2015).…”

Section: Hematopoietic Stem Cell Based Drugsmentioning

confidence: 99%

Stem cell drugs: the next generation of pharmaceutical products

Pham

2016

Biomed Res Ther

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Stem cells represent a new treatment option in medicine and pharmacy. Stem cells have been increasingly used for the treatment of many diseases. In fact, they have spurred a new age of medicine called regenerative medicine. In recent years, regenerative medicine has become a new revolution in disease treatment, especially with the use of stem cell drugs. Stem cell drugs refer to live stem cell based products that used as drugs for particular diseases. Unlike autologous stem cell transplantation, stem cell drugs are "off-the-shelf" products that are ready to be used without requirement of any further manipulation. This review aims to summarize some of the approved stem cell drugs, and discuss the revolution of regenerative medicine and personalized medicine. As well, the review will discuss how stem cell drugs have led to a new direction in stem cell therapy, providing a new platform for patient needs.

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“…6 MSC-derived exosomes (MSC-Ex), membrane-enclosed vesicles found in MSC-conditioned medium (MSC-CM), have been reported to contribute to angiogenesis, neurite outgrowth, and skeletal muscle regeneration. [7][8][9] We previously demonstrated that hucMSCs and hucMSC-Ex could alleviate liver fibrosis, promote liver and renal injury repair, and improve wound healing. [10][11][12] hucMSC-Ex may have similar protective and reparative properties as their cellular counterparts in tissue repair.…”

Section: Introductionmentioning

confidence: 99%

hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury

et al. 2017

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Exosomes are small biological membrane vesicles secreted by various cells, including mesenchymal stem cells (MSCs). We previously reported that MSC-derived exosomes (MSC-Ex) can elicit hepatoprotective effects against toxicant-induced injury. However, the success of MSC-Ex-based therapy for treatment of liver diseases and the underlying mechanisms have not been well characterized. We used human umbilical cord MSC-derived exosome (hucMSC-Ex) administrated by tail vein or oral gavage at different doses and, in engrafted liver mouse models, noted antioxidant and anti-apoptotic effects and rescue from liver failure. A single systemic administration of hucMSC-Ex (16 mg/kg) effectively rescued the recipient mice from carbon tetrachloride (CCl 4 )-induced liver failure. Moreover, hucMSC-Ex-derived glutathione peroxidase1 (GPX1), which detoxifies CCl 4 and H 2 O 2 , reduced oxidative stress and apoptosis. Knockdown of GPX1 in hucMSCs abrogated antioxidant and anti-apoptotic abilities of hucMSC-Ex and diminished the hepatoprotective effects of hucMSC-Ex in vitro and in vivo. Thus, hucMSC-Ex promote the recovery of hepatic oxidant injury through the delivery of GPX1.

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Mesenchymal‐stem‐cell‐derived exosomes accelerate skeletal muscle regeneration

Cited by 443 publications

References 31 publications

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

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

Stem cell drugs: the next generation of pharmaceutical products

hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury

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