Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src
作者机构：Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina Department of Genetics and Cell BiologyBasic medical collegeQingdao University308 Ningxia Road266071QingdaoChina Research Institute of the McGill University Health CentreGlen SiteMcGill UniversityMontrealQCH4A 3J1Canada Department of Cell BiologySchool of Life SciencesShanghai University200444ShanghaiChina
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2021年第6卷第11期
页 面：3318-3332页
核心收录：
学科分类：0710[理学-生物学] 07[理学] 071008[理学-发育生物学]
基 金：This study was supported by the National Natural Science Foundation of China(No.81902848) the Fundamental Research Funds for the Central University(3332019062) CAMS Innovation Fund for Medical Sciences(2017-I2M-3-007) The National Key Research and Development Program of China(2016YFA0101000,2016YFA0101003,2018YFA0109800) the 111 Project(B18007)
摘 要：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.
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