Exosomes secreted by macrophages upon copper ion stimulation can promote angiogenesis

Copper, a frequently used additive of implant materials, can alter macrophage phenotype thus directing the fate of the implants. Exosomes, secreted by mammalian cells, can target to recipient cells and mediate their functions. However, whether exosomes derived from macrophages upon copper ion stimulation can modulate angiogenesis, a key index for implant osseointegration, is still unclear. Herein, the influence of copper ions on macrophage-derived exosome secretion, ingestion behavior by endothelial cells, and angiogenic-induction ability is investigated. The results show copper ions (0–100 μM) have little influence on the secretion of macrophage-derived exosomes. Endothelial cells can uptake the exosomes from all the groups in a time-dependent manner. The exosomes have little influence on endothelial adhesion and proliferation, but can upregulate angiogenic ability of endothelial cells in vitro and in vivo , which may be related to trafficking of integrin β1. The results provide insight into the effect of copper ions on immunomodulatory mechanism of macrophages, which is important for implant design from the perspective of material compositions. • Copper ions have no influence on macrophage exosome secretion. • Endothelial cells can ingest exosomes secreted by macrophages, irrespective of copper ion stimulation. • The exosomes derived from macrophages upon copper ion stimulation can promote angiogenesis.