Introduction

Aging is the predominant risk factor for degenerative diseases and conditions that limit health span. Among degenerative rheumatic diseases, the most prevalent is osteoarthritis (OA), which is characterized by the loss of joint function and the dysregulation of several physiological processes. Senescence has been reported to be one of the main drivers of OA pathogenesis, in particular via the release of senescence-associated secretory phenotype (SASP) factors. Understanding senescence occurrence in OA might help to develop novel approaches for treating the disease.

Content

SASP factors are released by chondrocytes, synoviocytes and other joint tissues contributing to disease development and senescent phenotype dissemination. However, the exact mechanism connecting senescence and OA pathology remains unclear. The role of EVs in the propagation of SASP factors and the induction of senescence in the microenvironment and systemically will be discussed in the context of OA.

By contrast to their role in disease dissemination, EVs can have a pro-regenerative role and their rejuvenating function has been demonstrated using EVs from young cells injected into aged animals. This function has been exemplified in vitro using EVs isolated from mesenchymal stromal cells (MSC-EVs). Indeed, infant MSC-EVs or umbilical cord-derived MSC-EVs can rejuvenate elderly or senescing MSCs, as shown by reduced number of senescent cells and ROS accumulation as well as increased self-renewal capacity, telomere length and proliferation rate. Therefore, the possibility that MSC-EVs might exert a senoprotective effect is being investigating. Few data exist on a direct effect of MSC-EVs on OA-associated senescence. A single report on the effect of MSC secretome on the senescent phenotype of OA chondrocytes used the conditioned medium of MSCs.

In the team, we previously demonstrated that MSC-EVs largely mediate the therapeutic effect of parental cells using an in vitro model of OA chondrocytes and in vivo using the collagenase-induced model of OA (CIOA). We will present our recent data on the senoprotective function of MSC-EVs in a new model of etoposide-induced senescence in OA chondrocytes. We used etoposide to induce DNA damage-associated senescence, which was characterized by growth arrest, increase of SA-βGal⁺ cell number, increase of p15, p21, p27 expression, of nuclear γH2AX foci, of stress fibers and cell surface confirming the induction of main senescence features. The addition of different doses of ASC-EVs at the time of senescence induction prevented the increase of SA-βGal⁺ cell number and significantly reduced the number of γH2AX⁺ chondrocytes as well as their nucleus surface. No effect of ASC-EVs was found on CDKI expression whereas the secretion of several SASP factors (IL6, IL8, MMP3, MMP13, HGF, VEGF) was decreased. Interestingly, ASC-EVs slightly up-regulated the anabolic markers of chondrocytes (AGG and type II COLLAGEN) and decreased the expression of catabolic markers (MMP13, AP). The results demonstrate that MSC-EVs exert a senoprotective and chondroprotective effect on OA chondrocytes.

Finally, we will present data on the impact of senescence induction in MSCs and their derived EVs on their therapeutic function in vitro and in vivo models of OA.

References

Boulestreau J, Maumus M, Jorgensen C, Noël D. Extracellular vesicles from mesenchymal stromal cells: therapeutic perspectives for senescence targeting in osteoarthritis. Advanced Drug Delivery Reviews, 2021, 113836.

Acknowledgments

Study was supported by a research grant from FOREUM, Foundation for Research in Rheumatology.