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

Autor:	Wijesinghe SN; Institute of Inflammation and Ageing, MRC- Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom., Anderson J; Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom., Brown TJ; School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom., Nanus DE; Institute of Inflammation and Ageing, MRC- Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom., Housmans B; Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University Medical Center, Maastricht, Netherlands., Green JA; University of Liverpool, Liverpool, United Kingdom., Hackl M; TAmiRNA GmbH, Vienna, Austria., Choi KK; School of Medicine, University of Nottingham, Nottingham, United Kingdom., Arkill KP; School of Medicine, University of Nottingham, Nottingham, United Kingdom., Welting T; Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University Medical Center, Maastricht, Netherlands., James V; School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom., Jones SW; Institute of Inflammation and Ageing, MRC- Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom., Peffers MJ; Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2022 Sep 23; Vol. 9, pp. 971621. Date of Electronic Publication: 2022 Sep 23 (Print Publication: 2022).
DOI:	10.3389/fmolb.2022.971621
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Wijesinghe, Anderson, Brown, Nanus, Housmans, Green, Hackl, Choi, Arkill, Welting, James, Jones and Peffers.)
Databáze:	MEDLINE
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