Cellular and molecular mechanisms driving modulation of immune responses by umbilical cord-derived mesenchymal stromal cells

Mesenchymal Stromal Cells MSC are a population of multipotent stem cells with a high potential for tissue regeneration. Due to the high availability in tissues such as bone marrow or adipose or umbilical corde tissue and the simplicity of cell culture and handling, MSCs has become a widely used therapeutic alternative for cell therapy in orthopedia, hematology, cardiology and neurology. Besides its high differentiation capacity towards osteo-articular cell lineages, MSCs harbour potent immunomodulatory properties that make them potentially effective in the context of immflammatory and autoimmune disorders. Several mechanisms of immunemodulation have been demonstrated in bone marrow and adipose tissue MSCs mainly involving expression and secretion of regulatory cytokines directed to components of the innate and adaptive immunity. At cellular level, MSCs regulate the expression of hystocompatibility molecules, inhibit activation of dendritic cells and effector lymphocytes and activate regulatory T cells thereby inducing potent anti-immflamatory signals. Although well described, cellular and molecular immunological pathways vary from MSC type and stage of differentiation and the mechanisms involved are not fully dilucidated yet. One of the most attractive anti-immflamatory pathways involve the production of extracellular vesicles EV by cultured MSCs. EVs are sub-micron vesicles made of bilipidic membrane and proteins that carry several cytoplasmic elements including nucleic acids and soluble proteins. EVs are produced by several types of cells to deliver signals of different nature to target cells hence modifying their fate. EVs can be classified according to diameter, being microparticles MP above 200 nm and exosomes between 40 and 200 nm. Recent studies have demonstrated potent anti immflamatory responses mediated by EVS derived from bone marrow MSC in vitro and in vivo. However specific immunomodulatory mechanisms mediated by EV on human immune cells remain to be clarified. Even less is known about the properties of EVs secreted MSC obtained from umbilical cord wharton jelly WJ, a new and attractive source of MSC with stronger regenerative potential for future clinical applications. In this proposal we want to characterize human EVs produced by WJ-MSCs in terms of biosynthesis, content and modulatory effect on immune responses in different immune cell populations.