Date Published: May 19, 2018
Publisher: Impact Journals
Author(s): Lucia Terlecki-Zaniewicz, Ingo Lämmermann, Julie Latreille, Madhusudhan Reddy Bobbili, Vera Pils, Markus Schosserer, Regina Weinmüllner, Hanna Dellago, Susanna Skalicky, Dietmar Pum, Juan Carlos Higareda Almaraz, Marcel Scheideler, Frédérique Morizot, Matthias Hackl, Florian Gruber, Johannes Grillari.
Loss of functionality during aging of cells and organisms is caused and accompanied by altered cell-to-cell communication and signalling. One factor thereby is the chronic accumulation of senescent cells and the concomitant senescence-associated secretory phenotype (SASP) that contributes to microenvironment remodelling and a pro-inflammatory status. While protein based SASP factors have been well characterized, little is known about small extracellular vesicles (sEVs) and their miRNA cargo. Therefore, we analysed secretion of sEVs from senescent human dermal fibroblasts and catalogued the therein contained miRNAs. We observed a four-fold increase of sEVs, with a concomitant increase of >80% of all cargo miRNAs. The most abundantly secreted miRNAs were predicted to collectively target mRNAs of pro-apoptotic proteins, and indeed, senescent cell derived sEVs exerted anti-apoptotic activity. In addition, we identified senescence-specific differences in miRNA composition of sEVs, with an increase of miR-23a-5p and miR-137 and a decrease of miR-625-3p, miR-766-3p, miR-199b-5p, miR-381-3p, miR-17-3p. By correlating intracellular and sEV-miRNAs, we identified miRNAs selectively retained in senescent cells (miR-21-3p and miR-17-3p) or packaged specifically into senescent cell derived sEVs (miR-15b-5p and miR-30a-3p). Therefore, we suggest sEVs and their miRNA cargo to be novel, members of the SASP that are selectively secreted or retained in cellular senescence.
Accumulation of senescent cells with age and at sites of age-associated diseases has been observed in the context of cardiovascular diseases, neurodegenerative disease, skin conditions and others . Importantly, their removal in transgenic mice [2–4] or by senolytics [5,6] leads to later onset of several age-associated diseases [2,7–9].
Accumulation of senescent cells is considered to drive several age-associated diseases. One of the characteristic of senescent cells that is considered to contribute to this phenomenon, is the cumulative secretion of several proteins involved in inflammation, growth promoting signaling and extracellular matrix remodeling, which is generally summarized under the term SASP . With increasing numbers of reports on secretory miRNAs describing their almost ‘hormonal’ action on recipient cells  and their potential as biomarkers or therapeutic targets for age-associated diseases , the question arises whether secreted miRNAs, especially those enclosed in EVs, might also be part of the SASP.
Detailed experimental procedures are provided in the supplementary information.