Senescent cells (SnCs) are increasingly recognized as central effector cells in age-related pathologies. Extracellular vesicles (EVs) are potential cellular communication tools through which SnCs exert central effector functions in the local tissue environment. To test this hypothesis in a medical indication that could be validated clinically, Johns Hopkins University researchers evaluated EV production from SnCs enriched from chondrocytes isolated from human arthritic cartilage. EV production increased in a dose-responsive manner as the concentration of SnCs increased. The EVs were capable of transferring senescence to nonsenescent chondrocytes and inhibited cartilage formation by non-SnCs. The researchers used microRNA (miR) sequencing to show that miR profiles of EVs isolated from human arthritic synovial fluid did not fully overlap with the senescent chondrocyte EV profiles. The effect of SnC clearance was tested in a murine model of posttraumatic osteoarthritis. miR and protein profiles changed after senolytic treatment but varied depending on age. In young animals, senolytic treatment altered expression of miR-34a, -30c, -125a, -24, -92a, -150, and -186, and this expression correlated with cartilage production. The primary changes in EV contents in aged mice after senolytic treatment, which only reduced pain and degeneration, were immune related. In sum, EV contents found in synovial fluid may serve as a diagnostic for arthritic disease and indicator for therapeutic efficacy of senolytic treatment.
(A) Representative electron micrographs of EVs derived from OA chondrocytes treated with vehicle (veh) and UBX0101. Scale bar: 200 nm. (B and C) Mean size and concentration of EV enrichments released per cell in human OA chondrocytes at 1, 2, 4, and 6 days after incubation with veh or 43 μM UBX0101, (D) Heatmap and hierarchical clustering depicting statistically significant (P < 0.1 by t test) differentially expressed miRs.
Jeon OH, Wilson DR, Clement CC, Rathod S, Cherry C, Powell B, Lee Z, Khalil AM, Green JJ, Campisi J, Santambrogio L, Witwer KW, Elisseeff JH. (2019) Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight 4(7). pii: 125019. [article]