Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126

Liu, Wei; Li, Linwei; Rong, Yuluo; Qian, Dingfei; Chen, Jian; Zhou, Zheng; Luo, Yi; Jiang, Dongdong; Cheng, Lin; Zhao, Shujie; Kong, Fanqi; Wang, Jiaxing; Zhou, Zhimin; Xu, Tao; Gong, Fangyi; Huang, Yifan; Gu, Changjiang; Zhao, Xuan; Bai, Jianling; Wang, Feng; Zhao, Wene; Zhang, Le; Li, Xiaoyan; Yin, Guoyong; Fan, Jin; Cai, Wei

doi:10.1016/j.actbio.2019.12.020

Cited by 280 publications

(285 citation statements)

References 73 publications

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“…Moreover, hypoxia preconditioning mediated enhanced production of exosomal miR-126 through the activation of hypoxia inducible factor 1 (HIF-1α). Hypoxia preconditioning represents a promising method for optimizing the therapeutic actions of MSC-exosomes in bone fracture healing (Liu et al, 2020). These findings verify the vital regulatory role of MSCs-EV in bone fracture healing, identifying it as a potential therapeutic method for bone fracture.…”

Section: Mscs-ev and Bone Fracturesupporting

confidence: 61%

The Application of MSCs-Derived Extracellular Vesicles in Bone Disorders: Novel Cell-Free Therapeutic Strategy

Liu

Liang

et al. 2020

Front. Cell Dev. Biol.

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Bone is crucial for supporting the body, protecting other organs, providing minerals, and secreting hormone to regulate other organ's function. Bone disorders result in pain and disability, severely affecting human health, reducing the quality of life and increasing costs to society. With the rapid increase in the aging population worldwide, bone disorders have become one major disease. As a result, efficacious therapies of bone disorders have become the focus of attention worldwide. Mesenchymal stem cells (MSCs) have been widely explored as a new therapeutic method for numerous diseases. Recent evidence suggests that the therapeutic effects of MSCs are mainly mediated by their extracellular vesicles (EV). MSCs-derived extracellular vesicles (MSCs-EV) is indicated as a novel cell-free alternative to cell therapy with MSCs in regenerative medicine. Here, we review the current knowledge of EV and highlight the application studies of MSCs-EV in bone disorders by focusing on osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and bone fracture. Moreover, we discuss the key issues and perspectives of MSCs-EV as a clinical therapeutic strategy for bone diseases.

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Section: Mscs-ev and Bone Fracturesupporting

confidence: 61%

The Application of MSCs-Derived Extracellular Vesicles in Bone Disorders: Novel Cell-Free Therapeutic Strategy

Liu

Liang

et al. 2020

Front. Cell Dev. Biol.

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“…In recent years, research has focused on the application of MSC-derived exosomes in the field of tissue engineering, inflammation modulation, regeneration medicine etc. [35][36][37][38]. Our studies have shown that exosomes derived from MSCs could enhance functional recovery after SCI by inhibiting neuroinflammation and promoting axonal regeneration [39,40].…”

Section: Introductionmentioning

confidence: 82%

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

Liu

Rong

Wang

et al. 2020

J Neuroinflammation

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Background: Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism. Methods: Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms. Results: Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain-and loss-offunction experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p. Conclusion: Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.

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“…91 The exosomes from hypoxically preconditioned MSCs had a higher miR-126 level and promoted fracture healing via the SPRED1/Ras/Erk signaling pathway. 92 The injection of BMSC-derived exosomes can rescue the retardation of fracture healing in the femur fracture model of CD9(−/−) mice. 93 Similarly, BMSC-derived exosomes can enhance osteogenesis and angiogenesis partially through the BMP-2/Smad1/RUNX2 and HIF-1alpha/VEGF pathways at fracture sites to accelerate fracture repair in a femoral nonunion rat model.…”

Section: Exosomementioning

confidence: 99%

Exosomes: roles and therapeutic potential in osteoarthritis

Ni¹,

et al. 2020

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Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.

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Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126

Cited by 280 publications

References 73 publications

The Application of MSCs-Derived Extracellular Vesicles in Bone Disorders: Novel Cell-Free Therapeutic Strategy

The Application of MSCs-Derived Extracellular Vesicles in Bone Disorders: Novel Cell-Free Therapeutic Strategy

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

Exosomes: roles and therapeutic potential in osteoarthritis

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