Abstract
Mesenchymal stem or stromal cells (MSCs) exert chondroprotective effects in preclinical models of osteoarthritis (OA). Most of their therapeutic effects are mediated via soluble mediators, which can be conveyed within extracellular vesicles (EVs). The objective of the study was to compare the respective role of exosomes (Exos) or microvesicles/microparticles (MPs) in OA. MPs and Exos were isolated from bone marrow murine BM-MSCs through differential centrifugation. Effect of MPs or Exos was evaluated on OA-like murine chondrocytes and chondroprotection was quantified by RT-qPCR. In OA-like chondrocytes, BM-MSC-derived MPs and Exos could reinduce the expression of chondrocyte markers (type II collagen, aggrecan) while inhibiting catabolic (MMP-13, ADAMTS5) and inflammatory (iNOS) markers. Exos and MPs were also shown to protect chondrocytes from apoptosis and to inhibit macrophage activation. In vivo, Exos or MPs were injected in the collagenase-induced OA (CIOA) model and histomorphometric analyses of joints were performed by µCT and confocal laser microscopy. BM-MSCs, MPs and Exos equally protected mice from joint damage. In conclusion, MPs and Exos exerted similar chondroprotective and anti-inflammatory function in vitro and protected mice from developing OA in vivo, suggesting that either Exos or MPs reproduced the main therapeutic effect of BM-MSCs.
Highlights
Osteoarthritis (OA) is the most prevalent rheumatic disease, characterized by cartilage degradation, sub-chondral bone sclerosis, osteophyte formation, synovial inflammation and calcification of ligaments
Size of both extracellular vesicles (EVs) preparations was measured by Dynamic Light Scattering (DLS) and found to peak at 488 nm for MPs and 96 nm for Exos (Fig. 1B)
Because TGF-β is a potent inducer of chondrocyte anabolism, we evaluated the effect of TGF-β3 pre-activation of BM-Mesenchymal stem or stromal cells (MSCs) in this assay
Summary
Osteoarthritis (OA) is the most prevalent rheumatic disease, characterized by cartilage degradation, sub-chondral bone sclerosis, osteophyte formation, synovial inflammation and calcification of ligaments. There are three main classes: exosomes or small-size vesicles, microparticles or microvesicles and apoptotic bodies They are characterized by their size, biogenesis and expression of membrane markers. In the most recent article, a beneficial effect of embryonic stem cell-derived Exos was reported in the destabilization of the medial meniscus (DMM) model[13]. None of these studies reported the effect of other types of EVs. One objective of the present study was to characterize in vitro the functional role of either Exos or MPs isolated from bone marrow (BM-MSCs) on the function of cells from the articular environment, chondrocytes and monocytes/ macrophages. The second objective was to characterize in depth the in vivo therapeutic effect of the two types of EVs in a preclinical model of OA using quantitative histomorphometric parameters of bone and cartilage tissues
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