Research Paper Volume 10, Issue 5 pp 1103—1132

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

Lucia Terlecki-Zaniewicz 1, 2, , Ingo Lämmermann 1, 2, , Julie Latreille 3, , Madhusudhan Reddy Bobbili 2, , Vera Pils 1, 2, , Markus Schosserer 2, , Regina Weinmüllner 1, 2, , Hanna Dellago 9, , Susanna Skalicky 9, , Dietmar Pum 10, , Juan Carlos Higareda Almaraz 5, 6, 7, 8, , Marcel Scheideler 5, 6, 7, 8, , Frédérique Morizot 3, , Matthias Hackl 9, , Florian Gruber 1, 4, , Johannes Grillari 1, 2, ,

  • 1 Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria
  • 2 Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
  • 3 Department of Biology and Women Beauty, Chanel R&T, Pantin, France
  • 4 Division for Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria
  • 5 Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  • 6 Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany
  • 7 Molecular Metabolic Control, Medical Faculty, , Germany
  • 8 German Center for Diabetes Research (DZD), Neuherberg, Germany
  • 9 TAmiRNA GmbH, Vienna, Austria
  • 10 Department of Nanobiotechnology, University of Natural Resources and Life Sciences, Vienna, Austria

received: February 16, 2018 ; accepted: May 10, 2018 ; published: May 19, 2018 ;

https://doi.org/10.18632/aging.101452
How to Cite

Copyright: Terlecki-Zaniewicz et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

Abbrevations: BH: Benjamini and Hochberg (BH) procedure; BrdU: bromodeoxyuridine; CDKN2A: cyclin-dependent inhibitor 2A, p21CIP1; D7/21: day 7/21 after stress treatment/recovery; (s)EV: (small) extracellular vesicle; EV-miRNAs: miRNAs enclosed in extracellular vesicle; FC: fold change; FCS: fetal calf serum; FDR: false discovery rate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HDF: human dermal fibroblast; SEV: international society for extracellular vesicles; MCR: mean-centering restricted normalization; NTA: nanoparticle tracking analysis; RM: repeated measurements; SA: sEV-miRNA Senescence-associated miRNAs enclosed in small extracellular vesicles; SASP: Senescence-associated secretory phenotype; SA-β-gal: Senescence-associated β-galactosidase; SIPS: stress induced premature senescence; SVD: singular value decomposition; TPM: tags per million; TSG10: tumour-susceptibility protein.