Young BMSC-derived extracellular vesicles containing lncRNA sponging miR-1843a-5p to regulate Mob3a/YAP axis promote osteogenesis of senescent BMSCs

Abstract

Abstract Bone repair in elderly patients poses a huge challenge due to the age-related progressive degenerative decline in regenerative abilities attributed to the senescence of bone marrow stem cells (BMSCs). Stem cell extracellular vesicles-mediated therapy are increasingly acknowledged as a promising strategy for delaying senescence and promoting osteogenesis. Osteoinductive exosome (OI-exo) derived from young BMSCs was applied to treatment of aging bone regeneration and demonstrated to alleviate aging-related phenotypes and promote proliferation and osteogenic differentiation of senescent BMSCs in vitro. OI-exo-loaded hierarchical mesoporous bioactive glass (MBG) scaffold was applied in calvarial defect of aged rats and induced rapid bone formation and efficient enhancement in osteogenesis in vivo, though excess activity of bone resorption in senescent individuals remained a tremendous challenge in aged bone regeneration. The potential underlying mechanism of young extracellular vesicles-enhanced osteogenesis of old BMSCs was revealed that OI-exos were rich in lncRNA-ENSRNOG00000056625, which functioned as a promoter of YAP dephosphorylation and nuclear translocation, ultimately resulting in elevated proliferation and osteogenic differentiation and reduced senescence-related phenotypes. The findings herein revealed the competing endogenous RNA network lncRNA-ENSRNOG00000056625/miR-1843a-5p/Mob3a, and might provide novel insights into the extracellular vesicles-stimulated osteogenesis and the downstream YAP signaling as a potential critical pathway in aging bone regeneration.