Abstract
Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time‐related increasing in hippocampal neural stem cells (H‐NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell‐derived small extracellular vesicles (ESC‐sEVs) are intravenously injected into VD rats. ESC‐sEVs treatment significantly alleviates H‐NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT‐qPCR it is identified that several miRNAs including miR‐17‐5p, miR‐18a‐5p, miR‐21‐5p, miR‐29a‐3p, and let‐7a‐5p, that can inhibit mTORC1 activation, exist in ESC‐sEVs. ESC‐sEVs rejuvenate H‐NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H‐NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC‐sEVs treatment ameliorates H‐NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence‐related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC‐sEVs may be a novel cell‐free therapeutic tool for patients with VD, as well as other aging‐related diseases.
Highlights
ESC-Small extracellular vesicles (sEVs) treatment ameliorates hippocampal neural stem cells (H-NSCs) senescence by inhibiting mammalian target of rapamycin complex 1 (mTORC1) ture involved in the formation of cognition and is extremely sensitive to cerebral hypoperfusion
These results revealed that ESC-sEVs can restore cognitive of Vascular dementia (VD) rats and this effect may be mediated by ameliorating the senescence of H-NSCs
C (Supporting Information), the level of phosphorylated S6K1 (P-S6K1) was significantly down-regulated by rapamycin, and transcription factor EB (TFEB) mostly located in nucleus in senescent H-NSCs when treated with rapamycin. These results indicated that mTORC1 is activated in senescent H-NSCs and TFEB was retained in the cytoplasm, and ESC-sEVs increased TFEB nuclear translocation by inhibiting mTORC1 activation and promoted lysosome activation in senescent H-NSCs
Summary
Progressive cognitive and behavioral deterioration is the key characteristic of VD, we first detected the spatial learning and memory abilities by MWM.[25]. These data confirmed a time-related reduction of cognitive functions in VD. The percentage of differentiated neurons (β-III tubulin+ cells) in VD group was significantly reduced at each time point from 0.5 to 8 months (Figure S2b, Supporting Information) These results indicated that the proliferation and neuronal differentiation capacity of H-NSCs in VD group are decreased, which may responsible for H-NSCs and neurogenesis reduction. These results suggest that during the progress of VD, the senescence of H-NSCs resulted in their loss, neurogenesis reduction, and subsequently cognitive dysfunction
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