Exosomes derived from umbilical cord mesenchymal stem cells alleviate jaw bone marrow mesenchymal stem cells senescence and restore osteogenic differentiation potential
Hongkun Li, Nuo Xu, Shuaichen Li, Xinjing Wang, An‐Ping Li, Haihui Wang, Shuang Wu, Sunxin Zhou, Chuan Cai, Tong Zhang
Abstract
BACKGROUND: The age-related functional decline of bone marrow mesenchymal stem cells significantly impairs bone regeneration capacity. Exosomes derived from umbilical cord mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic agents in regenerative medicine and anti-aging research due to their bioactive cargo and low immunogenicity. This study investigated the rejuvenating potential of UCMSCs-derived exosomes (UCMSC-Exos) on senescent jaw bone marrow mesenchymal stem cells (JBMMSCs) and their ability to enhance bone repair in aged rats. METHODS: Senescent JBMMSCs were treated with UCMSC-Exos, and their effects on cellular senescence, proliferation, migration, and osteogenic capability were assessed using senescence-associated beta-galactosidase (SA-β-gal) staining, CCK8 assays, scratch assays, alizarin red S staining, alkaline phosphatase staining, RT-qPCR, ELISA and western blotting. The underlying mechanisms were explored through western blot analysis of autophagy markers and PI3K/AKT/mTOR pathway. For in vivo evaluation, calvarial defect models were established in aged rats, and the bone repair efficacy of UCMSC-Exos was assessed by micro-CT, histological staining, immunohistochemical staining for OCN and ALP, and immunofluorescence staining for OPN and OSX. RESULTS: UCMSC-Exos treatment markedly attenuated cellular senescence in JBMMSCs, as demonstrated by decreased SA-β-gal-positive cells and downregulation of key senescence-associated proteins (p53, p21, and p16) and pro-inflammatory cytokines (IL-6 and TNF-α). The exosome-treated cells showed significant improvements in proliferative capacity, migratory ability, and osteogenic differentiation potential compared to untreated controls. Mechanistically, UCMSC-Exos restored autophagy through modulation of the PI3K/AKT/mTOR signaling pathway, as demonstrated by altered protein expression. In rat calvarial defect models, UCMSC-Exos treatment resulted in better bone repair in aged rats. CONCLUSIONS: This study demonstrated that UCMSC-Exos could rejuvenate senescent JBMMSCs by activating autophagy via the regulation of PI3K/AKT/mTOR pathway, and enhance bone repair in aged rats. UCMSC-Exos hold potential as a cell-free therapeutic tool for anti-aging treatments and regenerative medicine, particularly for age-related skeletal disorders.