Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting Hoxa7/MAPK signaling axis

Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation, dysfunction of osteogenic and angiogenic differentiation, increased secretion of the senescence-associated secretory phenotype (SASP), which bring difficulties for bone repair. Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells (O-BMSCs) was considered as effective strategy for bone regeneration in aging microenvironment. Magnesium (Mg) ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence. In this study, Akermanite biocreamics (Akt) containing Mg ion as a model was demonstrated to promote osteogenesis and angiogenesis effects of O-BMSCs by activating the MAPK signaling pathway in vitro. Moreover, the enhanced osteogenesis effects might be attributed to enhanced Mg-containing Akt-mediated exosomal miR-196a-5p cargo targeting Hoxa7 and activation of MAPK signaling pathway. Furthermore, the in vivo study confirmed that 3D-printed porous Mg-containing Akt scaffolds effectively increased bone regeneration in cranial defects of aged rats. The current results indicated that the exosomal-miR-196a-5p/Hoxa7/MAPK signaling axis might be the potential mechanism underlying Akt-mediated osteogenesis. The exosome-meditaed therapy stimulated by the released Mg ion contained in Akt biocreamics or other biomaterials might serve as a candidate strategy for bone repair in aged individuals.