MiR-6924-5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength

Feng, Wei; Jin, Qian; Yang, Mingyu; Yang, He; Xu, Tao; Shi, Youxing; Bian, Xuting; Chen, Wan; Wang, Yunjiao; Wang, Huan; Ai-Ning, Yang; Li, Yan; Tang, Hong; Huang, Pan; Mu, Miduo; He, Gang; Zhou, Mei; Kang, Xin; Tang, Kanglai

doi:10.1016/j.biomaterials.2021.121242

Cited by 35 publications

(60 citation statements)

References 46 publications

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“…Among them, exosome‐derived miRNAs are recognized as important mediators of intercellular communication and potential candidates for disease therapy 40 . Additionally, studies have shown that gene manipulation of MSCs plays a stronger therapeutic role by changing the expression of their exosomes derived miRNA 41,42 . Therefore, whether some miRNAs specifically expressed in IL‐35‐ASCexos play a role in this process needs to be further explored, which will be the focus of our follow‐up research.…”

Section: Discussionmentioning

confidence: 99%

Exosomes: Potential executors of IL‐35 gene‐modified adipose‐derived mesenchymal stem cells in inhibiting acute rejection after heart transplantation

Guo

et al. 2022

Scand J Immunol

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Heart transplantation has become the only 'cure' for end-stage heart diseases, but acute allograft rejection is the major obstacle to the survival of patients.Our previous studies showed that gene-modified adipose-derived mesenchymal stem cells (IL-35-ASCs) can effectively inhibit graft rejection and prolong the survival of transplanted hearts in mice. This study further explored the mechanism of IL-35-ASCs, especially focusing on the important role of IL-35-ASC-derived exosomes (IL-35-ASCexos) in inhibiting acute rejection. IL-35-ASCs were constructed in vitro and pretreated with IL-35 neutralizing antibody and GW4869 (an inhibitor of neutral sphingomyelinase that impairs exosome biogenesis/release). Then, pretreated IL-35-ASCs and CD4 + T cells were cocultured in Transwell plates, and changes in regulatory T cells (Tregs) and cytokines were detected. Then, IL-35-ASCexos were extracted, identified and analysed, and their immunoregulatory effects on CD4 + T cells were studied through coculture experiments. Finally, IL-35-ASCexos were applied to a mouse heart transplantation model to investigate the therapeutic effects on acute rejection of the allograft. The coculture experiment showed that the IL-35-neutralizing antibody could not completely block the immunosuppressive function of IL-35-ASCs, while GW4869 could effectively reduce their immunoregulatory characteristics. Similar to IL-35-ASCs, IL-35-ASCexos also have powerful immunosuppressive properties, effectively upregulating the Treg ratio in vivo and in vitro and prolonging graft survival. As the main effectors of IL-35-ASCs, these findings highlight the therapeutic potential of IL-35-ASCexos in inhibiting acute cardiac rejection of the allograft. Although the specific mechanism remains unclear and needs to be further explored, IL-35-ASCexos therapy is expected to become a new method to inhibit acute graft rejection. How to cite this article: Guo H, Li B, Li N, et al. Exosomes: Potential executors of IL-35 gene-modified adipose-derived mesenchymal stem cells in inhibiting acute rejection after heart transplantation.

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Section: Discussionmentioning

confidence: 99%

Exosomes: Potential executors of IL‐35 gene‐modified adipose‐derived mesenchymal stem cells in inhibiting acute rejection after heart transplantation

Guo

et al. 2022

Scand J Immunol

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“…miRNAs have been reported to regulate multiple processes in bone, such as osteoblast and osteoclast proliferation and differentiation [ 67 ]. Recent studies have shown that exosomal miRNAs can regulate bone development [ 10 ], inhibit osteoclast activity [ 68 ] and improve fracture repair [ 26 ] by competitively inhibiting post-transcriptional gene expression. However, exosomes alone showed poor bone regeneration effects due to their limited osteogenic inductive ability [ 69 , 70 , 71 ].…”

Section: Mirnas Mediating the Regulation Of Bmsc-evs On Bone Metabolismmentioning

confidence: 99%

“…Recent studies have emphasized that, in addition to ncRNAs, a large number of mRNAs and functional structural proteins are enriched in exosomes [ 150 , 151 ], which suggests that BMSC-Exos may also participate in the regulation of bone metabolism through their encapsulated mRNA and protein components [ 68 ]. Scleraxis (Scx) is a helix-loop-helix transcription factor, and the overexpression of Scx promotes bone formation [ 152 , 153 ].…”

Section: Protein-modified Bmsc-evs Regulating Bone Metabolismmentioning

confidence: 99%

“…Scleraxis (Scx) is a helix-loop-helix transcription factor, and the overexpression of Scx promotes bone formation [ 152 , 153 ]. Wang et al [ 68 ] found that Scx is dynamically expressed in BMSCs during early tendon-bone healing. The local injection of exosomes derived from Scx-overexpressing BMSCs (BMSC-Scx) hindered osteoclastogenesis and inhibited abnormally activated peritunel osteolysis at the tendon-bone healing interface in a dose-dependent manner [ 68 ].…”

Section: Protein-modified Bmsc-evs Regulating Bone Metabolismmentioning

confidence: 99%

“…Wang et al [ 68 ] found that Scx is dynamically expressed in BMSCs during early tendon-bone healing. The local injection of exosomes derived from Scx-overexpressing BMSCs (BMSC-Scx) hindered osteoclastogenesis and inhibited abnormally activated peritunel osteolysis at the tendon-bone healing interface in a dose-dependent manner [ 68 ]. It is suggested that BMSC-Scx-Exos may be involved in regulating the function of osteoclasts, thereby affecting bone resorption.…”

Section: Protein-modified Bmsc-evs Regulating Bone Metabolismmentioning

confidence: 99%

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Effects of BMSC-Derived EVs on Bone Metabolism

et al. 2022

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Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and participating in various physiological and pathological processes. Among them, EVs derived from bone marrow mesenchymal stem cells (BMSC-EVs) have similar therapeutic effects to BMSCs, including repairing damaged tissues, inhibiting macrophage polarization and promoting angiogenesis. In addition, BMSC-EVs, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability and easy storage, thus providing a promising therapeutic strategy for many diseases. In particular, BMSC-EVs show great potential in the treatment of bone metabolic diseases. This article reviews the mechanism of BMSC-EVs in bone formation and bone resorption, which provides new insights for future research on therapeutic strategies for bone metabolic diseases.

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Tolerant and Rapid Endochondral Bone Regeneration Using Framework‐Enhanced 3D Biomineralized Matrix Hydrogels

Bai,

Liu,

Huang

et al. 2023

Advanced Science

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Tissue‐engineered bone has emerged as a promising alternative for bone defect repair due to the advantages of regenerative bone healing and physiological functional reconstruction. However, there is very limited breakthrough in achieving favorable bone regeneration due to the harsh osteogenic microenvironment after bone injury, especially the avascular and hypoxic conditions. Inspired by the bone developmental mode of endochondral ossification, a novel strategy is proposed for tolerant and rapid endochondral bone regeneration using framework‐enhanced 3D biomineralized matrix hydrogels. First, it is meticulously designed 3D biomimetic hydrogels with both hypoxic and osteoinductive microenvironment, and then integrated 3D‐printed polycaprolactone framework to improve their mechanical strength and structural fidelity. The inherent hypoxic 3D matrix microenvironment effectively activates bone marrow mesenchymal stem cells self‐regulation for early‐stage chondrogenesis via TGFβ/Smad signaling pathway due to the obstacle of aerobic respiration. Meanwhile, the strong biomineralized microenvironment, created by a hybrid formulation of native‐constitute osteogenic inorganic salts, can synergistically regulate both bone mineralization and osteoclastic differentiation, and thus accelerate the late‐stage bone maturation. Furthermore, both in vivo ectopic osteogenesis and in situ skull defect repair successfully verified the high efficiency and mechanical maintenance of endochondral bone regeneration mode, which offers a promising treatment for craniofacial bone defect repair.

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MiR-6924-5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength

Cited by 35 publications

References 46 publications

Exosomes: Potential executors of IL‐35 gene‐modified adipose‐derived mesenchymal stem cells in inhibiting acute rejection after heart transplantation

Exosomes: Potential executors of IL‐35 gene‐modified adipose‐derived mesenchymal stem cells in inhibiting acute rejection after heart transplantation

Effects of BMSC-Derived EVs on Bone Metabolism

Tolerant and Rapid Endochondral Bone Regeneration Using Framework‐Enhanced 3D Biomineralized Matrix Hydrogels

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