Mechanical Force Promotes Mitochondrial Transfer From Macrophages to BMSCs to Enhance Bone Formation

ABSTRACT Macrophages and bone marrow mesenchymal stem cells (BMSCs) share a close relationship within the osteoimmune microenvironment. During mechanically induced bone formation, macrophages respond to stimuli and regulate this microenvironment, influencing BMSCs' proliferation and differentiation. However, the underlying mechanisms remain incompletely understood. In our study, we employed a cellular tension system and found that mechanical tension altered mitochondrial dynamics in macrophages, leading to increased mitochondrial fission. Using a macrophage‐BMSC direct co‐culture system, we demonstrated that macrophages transferred mitochondria to BMSCs, a process enhanced by tension. This enhancement was associated with Drp1‐mediated mitochondrial fission, as Drp1 knockdown in macrophages abolished the effect. Additionally, using in vitro co‐culture and in vivo tibial injection models, we found that mitochondria‐rich extracellular vesicles (Mito‐EVs) secreted by mechanically stretched macrophages promoted BMSCs' osteogenesis and enhanced bone formation via the CD200 receptor (CD200R)‐CD200 interaction. Our findings reveal a pivotal role for mitochondrial transfer in promoting osteogenesis during mechanotransduction, highlighting a novel mechanism of intercellular communication in bone biology.