Rôle thérapeutique des vésicules extracellulaires des cellules stromales mésenchymateuses dans l'arthrose : impact de la sénescence

Age is the most important risk factor in the incidence of degenerative diseases, especially osteoarthritis (OA), which is characterized by the accumulation of senescent cells in joints. Currently, there is no cure for osteoarthritis. Among the therapeutic approaches that are being evaluated, the injection of adipose mesenchymal stromal cells (ASCs) has shown promising results in pre-clinical and clinical studies. They exert their regenerative properties through the secretion of mediators released into the extracellular medium or contained in extracellular vesicles (EV). The objective of my PhD thesis was to evaluate the impact of the age of ASCs used to produce EVs, in particular the impact of senescence(definition), on their therapeutic effect in osteoarthritis.We developed a model of senescent ASCs and showed that their EVs maintain the ability of EV from healthy ASCs to regulate in vitro the phenotype of human OA chondrocytes. By contrast, EV from senescent ASCs lose their therapeutic effect in the mouse model of collagenase-induced osteoarthritis. In parallel, we tested the senoprotective effect of EVs derived from healthy ASCs in two models of chondrocytes induced in senescence using either an inflammatory (IL1β or a DNA damage (etoposide) stimulus. In the two models, EV from healthy ASCs prevent the induction of senescence on chondrocytes suggesting that this mechanism plays a role in their beneficial effect in OA.In conclusion, we provided evidence that EV isolated from senescent ASCs lose their therapeutic properties in osteoarthritis and demonstrated a senoprotective effect of EVs from healthy ASCs on OA chondrocytes in vitro.