Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype

Abstract

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.

Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

“…More recent descriptions of the SASP have been expanded to include the secretion of EVs (Robbins, 2017;Takasugi, 2018). Extracellular vesicles derived from senescent cells exhibit multiple changes in cargo compared to healthy cells including changes in protein (Takasugi et al, 2017), and miRNA abundance (Terlecki-Zaniewicz et al, 2018). To date, studies have focused on changes in EV cargo and functions in vitro.…”

Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

“…There are increasing lines of evidence suggesting that sEVs may constitute part of the SASP by mediating paracrine effects on the nearby microenvironment 63,64 . A recent study using a Crereporter system demonstrated a positive correlation between sEV uptake and senescence activation, and identified IFITM3 within sEVs partially responsible for transmitting paracrine senescence to normal cells 65 .…”

Senescent cells: Living or dying is a matter of NK cells

“…Remarkably, EVs secreted from senescent cells have unique characteristics and contribute to regulate the behavior of recipient cells similarly to soluble SASP factors . By analyzing EVs from senescent human dermal fibroblasts, Terlecki‐Zaniewicz and colleagues have identified a set of selectively retained or secreted miRNAs and have shown that senescent cell‐derived EVs with their miRNA cargo contribute to an antiapoptotic environment in tissues where senescent cells accumulate . Furthermore, ovarian cancer‐derived exosomes expressing miRNA‐433 have the potential to modulate the tumor microenvironment by inducing cellular senescence in neighboring cells .…”

“…56,57 By analyzing EVs from senescent human dermal fibroblasts, Terlecki-Zaniewicz and colleagues have identified a set of selectively retained or secreted miRNAs and have shown that senescent cell-derived EVs with their miRNA cargo contribute to an antiapoptotic environment in tissues where senescent cells accumulate. 58 Furthermore, ovarian cancer-derived exosomes expressing miRNA-433 have the potential to modulate the tumor microenvironment by inducing cellular senescence in neighboring cells. 59 In addition to miRNA pattern, also protein profile significantly changes in senescent cell-derived exosomes, as described by a proteomic study demonstrating that EVs derived from drug-induced senescent breast cancer cells contain proteins involved in cell proliferation, ATP depletion, and apoptosis.…”