Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src
Xian Xiao 1, Meiqian Xu 1, Hongliang Yu 1,
Liping Wang 1, Xiaoxia Li 2, Janusz Rak 3, Shihua Wang 4, Robert Chunhua Zhao 5
6
Signal Transduct Target Ther.2021 Oct
22;6(1):354.doi: 10.1038/s41392-021-00765-3.
PMID: 34675187
Abstract
Senescent
endothelial cells (ECs) could impair the integrity of the blood vessel
endothelium, leading to vascular aging and a series of diseases, such as
atherosclerosis, diabetes. Preventing or mitigating EC senescence might serve
as a promising therapeutic paradigm for these diseases. Recent studies showed
that small extracellular vesicles (sEV) have the potential to transfer
bioactive molecules into recipient cells and induce phenotypic changes. Since
mesenchymal stem cells (MSCs) have long been postulated as an important source
cell in regenerative medicine, herein we investigated the role and mechanism of
MSC-derived sEV (MSC-sEV) on EC senescence. In vitro results showed that
MSC-sEV reduced senescent biomarkers, decreased senescence-associated secretory
phenotype (SASP), rescued angiogenesis, migration and other dysfunctions in
senescent EC induced by oxidative stress. In the In vivo natural aging and
type-2 diabetes mouse wound-healing models (both of which have senescent ECs),
MSC-sEV promoted wound closure and new blood vessel formation. Mechanically,
miRNA microarray showed that miR-146a was highly expressed in MSC-sEV and also
upregulated in EC after MSC-sEV treatment. miR-146a inhibitors abolished the
stimulatory effects of MSC-sEV on senescence. Moreover, we found miR-146a could
suppress Src phosphorylation and downstream targets VE-cadherin and Caveolin-1.
Collectively, our data indicate that MSC-sEV mitigated endothelial cell
senescence and stimulate angiogenesis through miR-146a/Src.