The emerging antioxidant paradigm of mesenchymal stem cell therapy

Abstract Mesenchymal stem cells (multipotent stromal cells; MSCs) have been under investigation for the treatment of diverse diseases, with many promising outcomes achieved in animal models and clinical trials. The biological activity of MSC therapies has not been fully resolved which is critical to rationalizing their use and developing strategies to enhance treatment efficacy. Different paradigms have been constructed to explain their mechanism of action, including tissue regeneration, trophic/anti-inflammatory secretion, and immunomodulation. MSCs rarely engraft and differentiate into other cell types after in vivo administration. Furthermore, it is equivocal whether MSCs function via the secretion of many peptide/protein ligands as their therapeutic properties are observed across xenogeneic barriers, which is suggestive of mechanisms involving mediators conserved between species. Oxidative stress is concomitant with cellular injury, inflammation, and dysregulated metabolism which are involved in many pathologies. Growing evidence supports that MSCs exert antioxidant properties in a variety of animal models of disease, which may explain their cytoprotective and anti-inflammatory properties. In this review, evidence of the antioxidant effects of MSCs in in vivo and in vitro models is explored and potential mechanisms of these effects are discussed. These include direct scavenging of free radicals, promoting endogenous antioxidant defenses, immunomodulation via reactive oxygen species suppression, altering mitochondrial bioenergetics, and donating functional mitochondria to damaged cells. Modulation of the redox environment and oxidative stress by MSCs can mediate their anti-inflammatory and cytoprotective properties and may offer an explanation to the diversity in disease models treatable by MSCs and how these mechanisms may be conserved between species. Significance statement The role of mesenchymal stem cells (MSCs) in ameliorating oxidative and nitrosative injury has received considerable attention in recent years. The reduction-oxidation (redox) environment regulates many physiological and pathophysiological mechanisms in cellular biology. Oxidative stress and redox imbalance are mediated by molecular constituents that are present in all living cells and share similar functions. The ability of MSCs to regulate these processes may offer an explanation to the diversity of disease models treatable by MSCs and to the effects of MSCs conserved between species. In this review, evidence of direct and indirect antioxidant mechanisms of MSC therapies is explored.