We have demonstrated the therapeutic interest of mesenchymal stromal cells (MSCs) for several rheumatic and autoimmune diseases: osteoarthritis (OA), rheumatoid arthritis (CIA) and systemic sclerosis (SSc). We have also reported that extracellular vesicles (EV) isolated from these cells reproduce the main beneficial effects of parental cells. We aim at developing optimized therapeutic strategies by identifying MSC subtypes with higher regenerative potential selected from high throughput omics approaches and generating engineered MSCs with enhanced properties. In vitro functional assays and in vivo non-clinical models are used to evaluate the optimized strategy using EVs derived from enhanced MSCs. The impact of disease-associated deleterious environment, in particular inflammation and senescence, is also investigated to decipher its role on MSC and EV functions. The objective is to enhance the knowledge on MSC and MSC-derived EV to provide innovative solutions for clinical translation with relevant therapeutic medicinal products.