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.

Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1β, IL-4, Nrf-2, and Oxidative Stress

“…Also, Stavely and Nurgali [ 51 ] and Kim et al [ 52 ] revealed that MSC can also promote activity of GPx in fibroblasts during oxidative stimuli. Besides, Huang et al [ 53 ] proved that IMC drug was highly effective in enhancing the GPx activity in the AIA animal model.…”

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

“…This leads to the secretion of an appropriate combination of bioactive molecules specific for a determined pathology [213]. In this sense, our research group and others have reported that the in vitro preconditioning of MSCs with pro-inflammatory cytokines induces the secretion of high levels of anti-inflammatory and antioxidant molecules [206,213,214]. The secretome derived from MSCs is made of both: (a) soluble bioactive molecules and (b) exosomes: small nanovesicles containing several cell components including proteins and microRNAs (miRNAs).…”

“…The secretome derived from MSCs has been used to treat drug consumption and relapse in animal models of drug addiction. Importantly, MSCs secrete catalase and superoxide dismutase and promote the up-regulation of glutathione peroxidase in treated tissues [214], which potentially prevents the oxidation of redox-sensitive glutamate transporters that promote consumption and relapse (see Section 2.3). Indeed, using an animal model of alcohol addiction, we demonstrated that the non-invasive intranasal administration of exosomes derived from preconditioned human MSCs (hMSCs) efficiently reached the brain and partially reproduced the relapse prevention effects observed after the administration of live MSCs [216], while the intranasal administration of the complete secretome (exosomes plus soluble molecules) derived from preconditioned hMSCs fully recapitulated the therapeutic effects of MSC administration including a 90% reduction of chronic alcohol intake, complete prevention of alcohol relapse, a full reversion of hippocampal oxidative stress and inflammation, and an increase of GLT-1 levels in NAcc [66].…”

Conditioned Medium from Canine Amniotic Membrane-Derived Mesenchymal Stem Cells Improved Dog Sperm Post-Thaw Quality-Related Parameters

“…Mesenchymal stem cells (MSCs) and their derivatives are commonly used in regenerative medicine and have proved their clinical efficacy in the treatment of infertility [ 22 , 23 , 24 ]. The MSCs enhance anti-oxidant defenses in several tissues, including testis [ 24 ], through the secretion of proteins that reduce ROS production by scavenging free radicals [ 24 , 25 ] and enhance mitochondrial function through the Akt1 pathway [ 26 ]. They also secrete anti-inflammatory molecules and growth factors that protect cells from apoptosis when exposed to injuries [ 27 , 28 ].…”