Extracellular vesicles from hypoxia preconditioned bone marrow mesenchymal stem cell improve peri-implant osteogenesis under type 2 diabetes condition.

PURPOSE: Poor peri-implant osseointegration of dental implants in patients with type 2 diabetes has become a major clinical challenge in recent years. BMSC (bone marrow mesenchymal stem cell)-derived extracellular vesicles may play an important role in peri-implant osseointegration, but the mechanism remains unclear. Improving the therapeutic effect of BMSC-derived extracellular vesicles and exploring their potential mechanisms can help provide new treatment strategies for dental implants in patients with type 2 diabetes.

METHODS

The extracellular vesicles derived from hypoxia (Hypo-EVs) or normoxia (Nor-EVs) preconditioned bone marrow mesenchymal stem cells (BMSCs) were co-cultured with BMSCs and human umbilical vein endothelial cells (HUVECs). The effect of extracellular vesicles on BMSCs cell proliferation was detected by CCK-8 assay and EdU assay, and the effect on angiogenesis ability of HUVECs was detected by wound healing assay, transwell migration assay, tube formation assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. A diabetic rat dental implant model was also established and the effect of extracellular vesicles on implant osseointegration was evaluated through micro-CT scanning and histological analysis. The differentially expressed miRNAs between Hypo-EVs and Nor-EVs were identified by high-throughput miRNA sequencing. Subsequently, the target genes and their roles in regulating angiogenesis were predicted and analyzed by bioinformatics analysis and dual luciferase reporter assay.

RESULTS

In vitro experiments indicated that hypoxia preconditioning could elevate extracellular vesicle production and promote cell proliferation of BMSCs and angiogenesis of HUVECs. Moreover, Hypo-EVs promoted peri-implant osteogenesis in rats with diabetes. Further investigation revealed the vital involvement of the miR-106b-5p/HIF-1α axis in promoting peri-implant osseointegration under high glucose condition.

CONCLUSION

Extracellular vesicles derived from hypoxia-preconditioned BMSCs could improve the peri-implant osseointegration in rats with diabetes by promoting cell proliferation and angiogenesis, and the miR-106b-5p/ HIF-1α axis could be the underlying mechanism.