Journal
CELL PROLIFERATION
Volume 52, Issue 5, Pages -Publisher
WILEY
DOI: 10.1111/cpr.12669
Keywords
adipose mesenchymal stem cells; bone regeneration; exosomes; gene delivery; miR-375
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Funding
- National Natural Science Foundation of China [81600834, 81772876]
- Beijing Natural Science Foundation [L182006]
- Project for Culturing Leading Talents in Scientific and Technological Innovation of Beijing [Z171100001117169]
- Innovative Fund for Doctoral Students [BMU2018BSS002]
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Objectives The present study aimed to investigate whether exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells (hASCs) could enhance bone regeneration. Materials and Methods Exosomes enriched with miR-375 (Exo [miR-375]) were generated from hASCs stably overexpressing miR-375 after lentiviral transfection and identified with transmission electron microscopy, nanosight and western blotting. The construction efficiency of Exo (miR-375) was evaluated with qRT-PCR and incubated with human bone marrow mesenchymal stem cells (hBMSCs) to optimize the effective dosage. Then, the osteogenic capability of Exo (miR-375) was investigated with ALP and ARS assays. Furthermore, dual-luciferase reporter assay and western blotting were conducted to reveal the underlying mechanism of miR-375 in osteogenic regulation. Finally, Exo (miR-375) were embedded with hydrogel and applied to a rat model of calvarial defect, and mu-CT analysis and histological examination were conducted to evaluate the therapeutic effects of Exo (miR-375) in bone regeneration. Results miR-375 could be enriched in exosomes by overexpressing in the parent cells. Administration of Exo (miR-375) at 50 mu g/mL improved the osteogenic differentiation of hBMSCs. With miR-375 absorbed by hBMSCs, insulin-like growth factor binding protein 3 (IGFBP3) was inhibited by binding to its 3 ' UTR, and recombinant IGFBP3 protein reduced the osteogenic effects triggered by Exo (miR-375). After incorporated with hydrogel, Exo (miR-375) displayed a slow and controlled release, and further in vivo analysis demonstrated that Exo (miR-375) enhanced the bone regenerative capacity in a rat model of calvarial defect. Conclusions Taken together, our study demonstrated that exosomes derived from miR-375-overexpressing hASCs promoted bone regeneration.
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