Migrasomes derived from Piezo1-activated mesenchymal stem cells with osteogenic and angiogenic activities alleviate osteoporosis: a novel therapeutic agent for bone regeneration

Osteoporosis is characterized by decreased bone mass and degraded bone microstructure. Piezo1, a mechanosensitive ion channel, has been demonstrated to be a key molecule mediating the transduction of mechanical stimuli into biological signals. Piezo1 activation has been shown to alleviate osteoporosis, but its underlying regulatory mechanisms remain incompletely clarified. Migrasomes secreted by migrating cells carry spatial positional information and play a crucial role in regulating intercellular communication. This study reveals that migrasomes possess the potential function of alleviating osteoporosis through Mendelian randomization (MR) analysis. In vivo experimental results indicate that Yoda1, a Piezo1-specific agonist, significantly promotes the secretion of migrasomes by mesenchymal stem cells (MSCs). This suggests that Piezo1-mediated migrasomes formation may be a crucial mechanism by which Yoda1 ameliorates osteoporosis. We further found that bone marrow MSCs (BMSCs) could secrete migrasomes. Moreover, migrasomes derived from Yoda1-pretreated BMSCs (Mig-Yoda1) are enriched with multiple functional proteins. Experiments demonstrate that Mig-Yoda1 significantly enhance osteogenesis and angiogenesis. Mechanistically, Mig-Yoda1 promotes osteogenesis by maintaining mitochondrial homeostasis and activating the PI3K/AKT signaling pathway. Finally, Mig-Yoda1 effectively alleviate bone loss in osteoporotic mice. In summary, this study reveals a regulatory association between Piezo1 and migrasomes biogenesis, while also confirming the potential therapeutic value of Mig-Yoda1 with integrated spatiotemporal multidimensional information as a cell-free therapeutic agent for osteoporosis. The study proposes a new approach and experimental evidence for the clinical treatment of osteoporosis.