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.
Highlights
Aging induced vascular dysfunctions play a critical role in the pathogenesis of a variety of age-related diseases, such as delayed wound healing, heart failure, diabetes, Alzheimer’s disease, and kidney diseases[1,2]
We performed immunofluorescence staining of SA-β gal and CD31 on aged mice and diabetes mice injected with phosphatebuffered saline (PBS) or mesenchymal stem cells (MSCs)-small extracellular vesicles (sEV), the results showed that MSC-sEV decreased senescent endothelial cells (ECs) number (Supplementary Fig. i–l)
We found that in senescent HUVECs, the MSC-sEV treatment protected against senescence-induced biomarkers and dysfunctions, improved angiogenesis, migration, and proliferation capacities, senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and reactive oxygen species (ROS) level
Summary
Aging induced vascular dysfunctions play a critical role in the pathogenesis of a variety of age-related diseases, such as delayed wound healing, heart failure, diabetes, Alzheimer’s disease, and kidney diseases[1,2]. Vascular diseases are the leading causes of severe long-term impairment and mortality in older adults[3,4]. Therapeutic strategies to reduce vascular diseases by preventing or eliminating vascular senescence are still required, despite years of intensive research[5]. Senescent endothelial cells (ECs) exhibit major changes in gene expression, cell replication and morphology, impair the integrity of the endothelium in vascular by influencing the endothelium’s regenerative and angiogenic capacities, reactivity and pathogenic progression, contributing to vascular aging diseases[6,7]. A range of factors can cause endothelial senescence; among them, oxidative stress has a major role[8]. H2O2 and high glucose are factors contributing to ECs senescence as oxidative stresses[9,10].
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