Mitochondrial components transferred by MSC-derived exosomes promoted bone regeneration under high salt microenvironment via DRP1/Wnt signaling

Bone homeostasis relies on the dynamic balance of osteoblast mediated bone construction and osteoclast based bone resorption processes, which has been reported to be controlled by various mineral ions. However, there is no direct evidence of the effect and the underlying mechanism of high salt stimulation on bone metabolism. In this study, we demonstrated that high salt stimulation promoted excessive mitochondrial fission mediated by DRP1 in mesenchymal stem cells (MSCs), which resulted in impaired mitochondrial morphology and function. Consequently, this impairment hindered the bone formation of MSCs, resulting in osteopenia in mice. Mechanically, the impaired property of MSCs by high salt was controlled by DRP1 mediated mitochondrial fission, which inhibited the classical Wnt signaling pathway. Furthermore, the osteogenic property of MSC decreased by high salt could be restored by exosomes to transfer the mitochondrial DNA into the impaired MSCs. This study not only provides new strategies for promoting bone regeneration, but also provides new insights for the effect and mechanism of exosome-mediated delivery. Overall design: Human primary bone marrow mesenchymal stem cells treated with or without 30mM NaCl for 48 hours.