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The role of extracellular vesicle miRNAs and tRNAs in synovial fibroblast senescence

Wijesinghe, Susanne N.; Anderson, James; Brown, Thomas J.; Nanus, Dominika E.; Housmans, Bas; Green, Jonathan A.; Hackl, Matthias; Choi, Katie K.; Arkill, Kenton P.; Welting, Tim; James, Victoria; Jones, Simon W.; Peffers, Mandy J.

Authors

Susanne N. Wijesinghe

James Anderson

Thomas J. Brown

Dominika E. Nanus

Bas Housmans

Jonathan A. Green

Matthias Hackl

Katie K. Choi

Tim Welting

Simon W. Jones

Mandy J. Peffers



Contributors

Abstract

Extracellular vesicles are mediators of intercellular communication with critical roles in cellular senescence and ageing. In arthritis, senescence is linked to the activation of a pro-inflammatory phenotype contributing to chronic arthritis pathogenesis. We hypothesised that senescent osteoarthritic synovial fibroblasts induce senescence and a pro-inflammatory phenotype in non-senescent osteoarthritic fibroblasts, mediated through extracellular vesicle cargo. Small RNA-sequencing and mass spectrometry proteomics were performed on extracellular vesicles isolated from the secretome of non-senescent and irradiation-induced senescent synovial fibroblasts. β-galactosidase staining confirmed senescence in SFs. RNA sequencing identified 17 differentially expressed miRNAs, 11 lncRNAs, 14 tRNAs and one snoRNA and, 21 differentially abundant proteins were identified by mass spectrometry. Bioinformatics analysis of miRNAs identified fibrosis, cell proliferation, autophagy, and cell cycle as significant pathways, tRNA analysis was enriched for signaling pathways including FGF, PI3K/AKT and MAPK, whilst protein analysis identified PAX3-FOXO1, MYC and TFGB1 as enriched upstream regulators involved in senescence and cell cycle arrest. Finally, treatment of non-senescent synovial fibroblasts with senescent extracellular vesicles confirmed the bystander effect, inducing senescence in non-senescent cells potentially through down regulation of NF-κβ and cAMP response element signaling pathways thus supporting our hypothesis. Understanding the exact composition of EV-derived small RNAs of senescent cells in this way will inform our understanding of their roles in inflammation, intercellular communication, and as active molecules in the senescence bystander effect.

Citation

Wijesinghe, S. N., Anderson, J., Brown, T. J., Nanus, D. E., Housmans, B., Green, J. A., …Peffers, M. J. (2022). The role of extracellular vesicle miRNAs and tRNAs in synovial fibroblast senescence. Frontiers in Molecular Biosciences, 9, Article 971621. https://doi.org/10.3389/fmolb.2022.971621

Journal Article Type Article
Acceptance Date Sep 6, 2022
Online Publication Date Sep 23, 2022
Publication Date Sep 23, 2022
Deposit Date Nov 22, 2022
Publicly Available Date Nov 28, 2022
Journal Frontiers in Molecular Biosciences
Electronic ISSN 2296-889X
Publisher Frontiers Media SA
Peer Reviewed Peer Reviewed
Volume 9
Article Number 971621
DOI https://doi.org/10.3389/fmolb.2022.971621
Keywords Biochemistry, Genetics and Molecular Biology (miscellaneous); Molecular Biology; Biochemistry
Public URL https://nottingham-repository.worktribe.com/output/11749390
Publisher URL https://www.frontiersin.org/articles/10.3389/fmolb.2022.971621/full

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