Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3

Abstract

Summary Senescence is a cellular phenotype present in health and disease, characterized by a stable cell-cycle arrest and an inflammatory response called senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that both the soluble factors and small extracellular vesicles (sEVs) are capable of transmitting paracrine senescence to nearby cells. Analysis of individual cells internalizing sEVs, using a Cre-reporter system, show a positive correlation between sEV uptake and senescence activation. We find an increase in the number of multivesicular bodies during senescence in vivo . sEV protein characterization by mass spectrometry (MS) followed by a functional siRNA screen identify interferon-induced transmembrane protein 3 (IFITM3) as being partially responsible for transmitting senescence to normal cells. We find that sEVs contribute to paracrine senescence.

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

“…EVs not only change quantity and quality with cell senescence but can also play a role in causing senescence through a variety of cargo [197]. Recent evidence demonstrates increased EV production in IPF lungs could potentially be produced by senescent cells; Moreover, these EVs carry cargo such as interferon-induced transmembrane protein 3 to promote paracrine senescence [198]. EV quantify increases in the IPF lungs, and EVs isolated from fibrotic lungs can augment fibroproliferation in bleomycin-injured mice [126,199].…”

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 . Several studies have showed that cellular secretion of sEVs is enhanced in certain situations such as oxidative stress, telomeric attrition, irradiation and hypoxia, conditions that can induce cellular senescence 62 .…”

“…Several studies have showed that cellular secretion of sEVs is enhanced in certain situations such as oxidative stress, telomeric attrition, irradiation and hypoxia, conditions that can induce cellular senescence 62 . Although senescent cells (including those developed from cancer cells) release significantly more EVs than their non-senescent counterparts, and carry molecules involved in key pathophysiological processes [65][66][67][68][69] , how stromal cells in the TME behave upon therapy-induced senescence (TIS) remains yet underexplored. Our data support that senescent stromal cells produce increased numbers of sEVs, which can be conceptually considered as part of the full SASP spectrum.…”

The Emerging Role of Senescence in Ocular Disease

“…Paracrine senescence via the SASP has been previously described as an important mechanism during senescence [125,147], although these studies do not differentiate between the effect of soluble factors secreted by the cells and EVs released. Furthermore, a recent study in human primary fibroblasts provides evidence that both the soluble factors and sEVs are responsible for mediating paracrine senescence [148]. An in-depth mass spectroscopic analysis of the published protein composition of soluble factor of senescence [125] and sEV proteomics [148] shows little correlation between both fractions, suggesting that although the downstream signaling is similar, the triggers inducing senescence are diverse.…”

“…Furthermore, a recent study in human primary fibroblasts provides evidence that both the soluble factors and sEVs are responsible for mediating paracrine senescence [148]. An in-depth mass spectroscopic analysis of the published protein composition of soluble factor of senescence [125] and sEV proteomics [148] shows little correlation between both fractions, suggesting that although the downstream signaling is similar, the triggers inducing senescence are diverse. A comprehensive proteomic database of soluble and exosome SASP factors (SASP Atlas), originating from multiple senescence inducers and cell types has appeared recently [149].…”