Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice

Aging is a degenerative process that leads to tissue dysfunction and death.Embryonic stem cells(ESCs)have great therapeutic potential for age-related diseases due to their capacity for self-renewal and plasticity.However,the use of ESCs in clinical treatment is limited by immune rejection,tumourigenicity and ethical issues.ESC-derived extracellular vesicles(EVs)may provide therapeutic effects that are comparable to those of ESCs while avoiding unwanted effects.Here,we fully evaluate the role of ESC-EVs in rejuvenation in vitro and in vivo.Using RNA sequencing(RNA-Seq)and microRNA sequencing(miRNA-Seq)screening,we found that miR-15b-5p and miR-290a-5p were highly enriched in ESC-EVs,and induced rejuvenation by silencing the Ccn2-mediated AKT/mTOR pathway.These results demonstrate that miR-15b-5p and miR-290a-5p function as potent activators of rejuvenation mediated by ESC-EVs.The rejuvenating effect of ESC-EVs was further investigated in vivo by injection into aged mice.The results showed that ESC-EVs successfully ameliorated the pathological age-related phenotypes and rescued the transcriptome profile of aged mice.Our findings demonstrate that ESC-EVs treatment can rejuvenate senescence both in vitro and in vivo and suggest the therapeutic potential of ESC-EVs as a novel cell-free alternative to ESCs for age-related diseases.