Adipose derived mesenchymal stromal cells (ASC) are adult stem cells exhibiting functional properties that have open the way for cell-based clinical therapies. Primarily, their capacity of multilineage differentiation has been explored in a number of strategies for skeletal tissue regeneration. More recently, MSCs have been reported to exhibit immunosuppressive as well as healing capacities, to improve angiogenesis and prevent apoptosis or fibrosis through the secretion of paracrine mediators including HGF, IL1RA, IL-6, PDL-1, TSG6, TGF-β1 and PGE2. In normal homeostasis, IL1Ra counterbalances the effect of IL1α and IL1β as a competitive receptor antagonist. MSC immunosuppressive effect is highly variable according to cell population heterogeneity. We compared gene expression of huMSC with high potential to inhibit T cells response with low efficient MSC through gene array. We identified a signature associated with high immunoregulatory function. High expression of ITPR1, NR4A3, ABCA1, LIPG ADAMTS4 as well as expression of CD109, ITGA10, IL6R was associated with increased T cell suppressive effect in vitro. We performed preclinical models of osteoarthritis, and showed that a local injection of ASC showed a reduction of synovitis, reduction of osteophytes, joint stabilization, reducing the score of cartilage lesions. We then investigated the role of iNOS, IL6 and IL1RA respectively using the inflammatory collagen-induced arthritis model. In contrast to wt MSCs, which reduced both the incidence and clinical signs of arthritis, IL1RA^–/– MSCs were not able to prevent arthritis progression and even worsened the arthritic symptoms. μCT analysis showed a protection against bone erosion by wt MSCs but not in IL1RA^–/–MSCs-treated mice. We found a decrease of the number of CD4+IFN-γ+ Th1 and CD4+IL-17+ Th17 lymphocytes in the spleens of wt MSCs-treated mice as compared to IL1RA^–/– MSCs-treated mice. This work was completed by toxicology data showing the excellent tolerance of the local injection of ADSC and biodistribution showing the persistence of cells after 6 months in murine models. We conducted a open-label phase 1 trial including 18 patients with severe osteoarthritis of the knee in failure of conventional therapies (62.5% were KL IV) at two sites, Montpellier and Wurzburg. Mean age was 61 years, with a 10 years history of knee OA. The patient received a single injection of autologous ASC 15 days after lipoaspiration (2.106, 107 or 5.107) through intra-articular injection. The primary outcome measure of effectiveness was patient-reported WOMAC pain subscores by VAS in the affected knee at week 12. Secondary outcome measures included Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT OARSI) responses. We observed a decrease of the VAS Pain (73±11mm day 0 to 32±23 month 3), and of WOMAC (50±18 to 25±7 month 3). This study confirms the feasibility and safety of local injection of autologous cells from adipose tissue and suggested that the most effective dose was 107 autologous cells. Moreover, a molecular signature associated with increase immunosuppressive potential is described.