Exosomes derived from macrophages upon Zn ion stimulation promote osteoblast and endothelial cell functions

Osteogenesis and angiogenesis are both important for implant osseointegration, which can be tailored by immunomodulation of macrophages. Zn, a novel biodegradable material, can modulate macrophage functions in its ionic form. However, whether macrophage-derived exosomes, novel carriers of intracellular communication, participate in the process is still unclear. The present work shows that Zn ions in the concentration range of 0-100 mu M have no significant influence on macrophage viability, proliferation, morphology, and secretion amount of exosomes, but generally downregulate the gene expression of both M1 and M2 markers. The exosomes can be ingested continuously by osteoblasts and endothelial cells. The osteoblasts show the highest alkaline phosphatase activity after ingesting the exosomes derived from macrophages upon 4 mu M Zn ion stimulation. In contrast, the endothelial cells migrate the furthest distance after ingesting the exosomes upon 20 mu M Zn ion stimulation. These results indicate that Zn ions may vary the composition of macrophage-derived exosomes, which in turn affects the osteogenesis and angiogenesis. These findings are meaningful for the surface design of immunomodulatory biomaterials from the perspective of macrophage-derived exosomes.