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

Michela Borghesan, Juan Fafián-Labora, Olga Eleftheriadou, Paula Carpintero-Fernández, Marta Paez-Ribes, Gema Vizcay-Barrena, Avital Swisa, Dror Kolodkin-Gal, Pilar Ximénez-Embún, Robert Lowe, Belen Martín-Martín, Hector Peinado, Javier Muñoz, Roland A. Fleck, Yuval Dor, Ittai Ben-Porath, Anna Vossenkamper, Daniel Muñoz-Espin, Ana O'Loghlen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

183 Scopus citations

Abstract

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. Borghesan et al. show that the soluble fraction and small extracellular vesicles (sEVs) mediate paracrine senescence. RNA sequencing and loxP reporter systems confirm sEV-mediated paracrine senescence, while preventing sEV release averts senescence. Mass spectrometry and functional analysis show that the IFN protein, IFITM3, is partially responsible for this phenotype.

Original languageAmerican English
Pages (from-to)3956-3971.e6
JournalCell Reports
Volume27
Issue number13
DOIs
StatePublished - 25 Jun 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

Keywords

  • DDIS
  • EV
  • IFITM3
  • OIS
  • aging
  • exosomes
  • fragilis
  • interferon
  • paracrine senescence
  • small extracellular vesicles

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