Researchers here show that miR-21 and miR-217 are important in the way in which senescent cells can encourage nearby cells to also become senescent. These microRNAs are carried between cells via extracellular vesicles, small membrane-bound packages of molecules that might constitute the bulk of cell signaling activity. The research community has of late given a lot more attention to vesicle based signaling in a number of contexts. It remains to be seen whether or not discoveries in this part of the field will lead, in the near future, to effective points of intervention in the matter of senescent cell accumulation with age or in cancer.
Cellular senescence is considered as a hallmark of ageing and a major risk factor for the development of the most common age-related diseases (ARDs). Senescent cells (SCs) are characterised by a significantly reduced replicative potential and by the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP), which involves the paracrine induction of a senescent state in younger cells through a "bystander effect". Since this effect fuels inflammaging - the systemic, low-grade, chronic inflammation that accompanies human ageing - it appears to be a critical step in SC accumulation during organismal ageing.
Senescence modulation by microRNAs (miRNAs) is a major senescence-related epigenetic mechanism. This has been suggested, among other findings, by the identification of discrete miRNA signatures associated with senescence in different cell types and by the fact that living cells can actively release extracellular vesicles (EVs), which contain different species and amounts of non-coding RNAs. EVs seem to reflect the molecular characteristics of their cells of origin and to modulate the phenotype of recipient cells both in a paracrine and in a systemic manner.
This study was devised to unravel the relative contribution of EVs released from senescent ECs in spreading pro-senescence signals to proliferating cells via their miRNA cargo. Based on the evidence that the in vitro replicative senescence of ECs substantially mimics the progressive age-related impairment of endothelial function described in vivo, we set out to identify the miRNAs that are differentially expressed in senescent and non-senescent human umbilical vein endothelial cells (HUVECs) and their EVs.
MicroRNA profiling of small EVs (sEVs) and large EVs demonstrated that senescent cells release a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and SIRT1. Treatment of control cells with senescent cell sEVs induced a miR-21/miR-217-related impairment of DNMT1-SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype, and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40-100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by senescent cell sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.