期刊
MOLECULAR THERAPY
卷 30, 期 1, 页码 816-830出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2021.08.008
关键词
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资金
- American Federation for Aging Research 2019 Irene Diamond Fund/AFAR postdoctoral transition award in aging [AFAR_61231257]
- VA Merit Review Award from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [BX002668]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [IK6BX004212, IK6 BX003778]
Inflammation plays a crucial role in age-related diseases, and the release of miRNAs from primed stem cells can inhibit neuro-inflammation.
Inflammation plays a key role in the development of age-related diseases. In Alzheimer's disease, neuronal cell death is attributed to amyloidbeta oligomers that trigger microglial activation. Stem cells have shown promise as therapies for inflammatory diseases-because of their paracrine activity combined with their ability to respond to the inflammatory environment. However, the mechanisms underlying stem cell-promoted neurological recovery are poorly understood. To elucidate these mechanisms, we first primed stem cells with the secretome of lipopolysaccharide- or amyloidbeta-activated microglia. Then, we compared the immunomodulatory effects of extracellular vesicles (EVs) secreted from primed and nonprimed stem cells. Our results demonstrate that EVs from primed cells are more effective in inhibiting microglia and astrocyte activation, amyloid deposition, demyelination, memory loss and motor and anxiety-like behavioral dysfunction, compared to EVs from non-primed cells. MicroRNA (miRNA) profiling revealed the upregulation of at least 19 miRNAs on primed-stem cell EVs. The miRNA targets were identified, and KEGG pathway analysis showed that the overexpressed miRNAs target key genes on the toll-like receptor-4 (TLR4) signaling pathway. Overall, our results demonstrate that priming mesenchymal stem cells (MSCs) with the secretome of activated microglia results in the release of miRNAs from EVs with enhanced immune regulatory potential able to fight neuro-inflammation.
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