Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles

Background:In the last years, several clinical trials have proved the safety and efficacy of adipose-derived stem/stromal cells (ASC) in contrasting osteoarthritis (OA). Since ASC act mainly through paracrine mechanisms, theirsecretome (conditioned medium, CM) represents a promising therapeutic alternative. ASC-CM is a complex cocktailof proteins, nucleic acids, and lipids released as soluble factors and/or conveyed into extracellular vesicles (EV). Here,we investigate its therapeutic potential in an in vitro model of OA.Methods:Human articular chondrocytes (CH) were induced towards an OA phenotype by 10 ng/ml TNFαin thepresence of either ASC-CM or EV, both deriving from 5 × 105cells, to evaluate the effect on hypertrophic, catabolic,and inflammatory markers.Results:Given the same number of donor cells, our data reveal a higher therapeutic potential of ASC-CMcompared to EV alone that was confirmed by its enrichment in chondroprotective factors among which TIMP-1and -2 stand out. In details, only ASC-CM significantly decreased MMP activity (22% and 29% after 3 and 6 days)and PGE2 expression (up to 40% at day 6) boosted by the inflammatory cytokine. Conversely, both treatmentsdown-modulated of ~ 30% the hypertrophic marker COL10A1.Conclusions:These biological and molecular evidences of ASC-CM beneficial action on CH with an induced OAphenotype may lay the basis for its future clinical translation as a cell-free therapeutic in the management of OA.