Extracellular vesicles in human skin: cross-talk from senescent fibroblasts to keratinocytes by miRNAs

Abstract Extracellular vesicles (EVs) and their miRNA cargo are intercellular communicators transmitting their pleiotropic messages between different cell types, tissues and body fluids. Recently, they have been reported to contribute to skin homeostasis and were identified as to our knowledge previously unreported members of the senescence-associated secretory phenotype (SASP) of human dermal fibroblasts. However, the role of EV-miRNAs in paracrine signaling during skin aging is yet unclear. Here we provide evidence for the existence of small EVs in human skin and dermal interstitial fluid using dermal open flow microperfusion and show that EVs and miRNAs are transferred from dermal fibroblasts to epidermal keratinocytes in 2D cell culture, as well as in human skin equivalents. We further show that the transient presence of senescent fibroblast derived small EVs accelerates scratch closure of epidermal keratinocytes, while long-term incubation impairs keratinocyte differentiation in vitro . Finally, we identify vesicular miR-23a-3p, highly secreted by senescent fibroblasts, as one contributor of the EV mediated effect on keratinocytes in in vitro wound healing assays. To summarize, our findings support the current view that EVs and their miRNA cargo are members of the SASP and thus regulators of human skin homeostasis during aging.