ESC-sEVs rejuvenate aging hippocampal NSCs by transferring SMADs to regulate the MYT1-Egln3-Sirt1 axis

Tissue stem cell senescence leads to stem cell exhaustion, which results in tissue homeostasis imbalance and a decline in regeneration capacity. However, whether neural stem cells (NSCs) senescence occurs and causes neurogenesis reduction during aging is unknown. In this study, mice at different ages were used to detect age-related hippocampal NSCs (H-NSCs) senescence, as well as the function and mechanism of embryonic stem cells derived small extracellular vesicles (ESC-sEVs) in rejuvenating H-NSCs senescence. We found a progressive cognitive impairment, as well as age-related H-NSCs senescence, in mice. ESC-sEVs treatment significantly alleviated H-NSCs senescence, recovered compromised self-renewal and neurogenesis capacities, and reversed cognitive impairment. Transcriptome analysis revealed that Myelin transcription factor 1 (MYT1) is downregulated in senescent H-NSCs but upregulated by ESC-sEV treatment. In addition, knockdown of MYT1 in young H-NSCs accelerated age-related phenotypes and impaired proliferation and differentiation capacities. Mechanistically, ESC-sEVs rejuvenated senescent H-NSCs partly by transferring SMAD4 and SMAD5 to activate MYT1, which downregulated Egln3, followed by activation of HIF2a, NAMPT, and Sirt1 successively. Taken together, our results indicated that H-NSCs senescence caused cellular exhaustion, neurogenesis reduction and cognitive impairment during aging, which can be reversed by ESC-sEVs. Thus, ESC-sEVs may be promising therapeutic candidates for age-related diseases. Overall design: NSCs mRNA profiles of passage 2, passage 10 treated with pbs, and passage 10 treated with ESC-sEVs