miR-10a, miR-30c, and miR-451a Encapsulated in Small Extracellular Vesicles Are Prosenescence Factors in Human Dermal Fibroblasts

Abstract

Although small extracellular vesicles (sEV) have been reported to play an important role in cellular senescence and aging, little is known about the potential role and function of microRNAs (miRNAs) contained within the sEV. To determine the senescence-associated factors secreted from sEV of human dermal fibroblasts (HDFs), we isolated and characterized sEV from nonsenescent versus that from senescent HDFs. Small RNA-sequencing analysis identified many enriched miRNAs in sEV of senescent HDF, as shown by the upregulation of miR-10a, miR-30c, and miR-451a and downregulation of miR-128, miR-184, miR-200c, and miR-125a. Over-expression of miR-10a, miR-30c, and miR-451a induced an aging phenotype in HDFs, whereas inhibition of these miRNAs reduced senescent-like phenotypes in senescent HDFs. Moreover, treatment with sEV or sEV-containing conditioned medium promoted cellular senescence in HDFs, whereas sEV depletion abrogated prosenescence effects of the senescent HDF secretome. Interestingly, prosenescence sEV miRNAs were found to have an essential role in regulating ROS production and mitophagy activation. Taken together, our results revealed miR-10a, miR-30c, and miR-451a as prosenescence factors that are differentially expressed in sEV of senescent HDFs, showing the essential role of sEV miRNAs in the biological processes of aging.