Molecular Characterization of Secreted Factors and Extracellular Vesicles-Embedded miRNAs from Bone Marrow-Derived Mesenchymal Stromal Cells in Presence of Synovial Fluid from Osteoarthritis Patients

SIMPLE SUMMARY: Osteoarthritis (OA) is a common and disabling condition affecting half billion people worldwide. To date, management has been only palliative and regenerative approaches based on mesenchymal stromal cells (MSCs) have therefore gained interest in the scientific and medical communities. One of the main obstacles for their translation into everyday practice is the lack of a thorough characterization of these biological products in the context of the disease. In this study, we aimed at dissecting the molecular signals released by MSCs in an environment resembling OA joints. The main findings are that MSCs in contact with synovial fluid of OA patients are able to release factors with anti-inflammatory and regenerative properties. These results will lay the foundations for a wider use of MSCs based products for regenerative medicine and hopefully slow down or halt progression of the disease in patients that, when pharmacological, biologic or surgical treatments fail, have prosthesis implant as the elective therapeutic option. ABSTRACT: Bone marrow-derived mesenchymal stromal cells (BMSCs)-based therapies show a great potential to manage inflammation and tissue degeneration in osteoarthritis (OA) patients. Clinical trials showed the ability to manage pain and activation of immune cells and allowed restoration of damaged cartilage. To date, a molecular fingerprint of BMSC-secreted molecules in OA joint conditions able to support clinical outcomes is missing; the lack of that molecular bridge between BMSC activity and clinical results hampers clinical awareness and translation into practice. In this study, BMSCs were cultured in synovial fluid (SF) obtained from OA patients and, for the first time, a thorough characterization of soluble factors and extracellular vesicles (EVs)-embedded miRNAs was performed in this condition. Molecular data were sifted through the sieve of molecules and pathways characterizing the OA phenotype in immune cells and joint tissues. One-hundred and twenty-five secreted factors and one-hundred and ninety-two miRNAs were identified. The combined action of both types of molecules was shown to, first, foster BMSCs interaction with the most important OA immune cells, such as macrophages and T cells, driving their switch towards an anti-inflammatory phenotype and, second, promote cartilage homeostasis assisting chondrocyte proliferation and attenuating the imbalance between destructive and protective extracellular matrix-related players. Overall, molecular data give an understanding of the clinical results observed in OA patients and can enable a faster translation of BMSC-based products into everyday clinical practice.