Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo

Abstract

1These authors contributed equally to this study.Abbreviations used: CAT, catalase; CM, conditioned medium; EAE, experimental autoimmune encephalomyelitis; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acid protein; GST, glutathione-S-transferase; MOG, myelin oligodendrocyte glycoprotein peptide; MS, multiple sclerosis; MSC, mesenchimal stem cell; MT, metallothionein; NeuN, neuronal nuclei; PARP-1, poly(ADP-ribose) polymerase-1; PBS, phosphate-buffered saline; RPMI, Royal Park Memorial Institute; SOD, superoxide dismutase. AbstractExperimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis, is characterized by demyelination, inflammation and neurodegeneration of CNS in which free radicals play a role. Recently, the efficacy of murine mesenchimal stem cells (MSCs) as treatment of EAE induced in mice by the encephalitogenic peptide MOG(35-55) was demonstrated. The present study analyzed some markers of oxidative stress, inflammation/degeneration and apoptosis such as metallothioneins (MTs), antioxidant enzymes (superoxide dismutase, catalase and glutathione-S-transferase), poly(ADP-ribose) polymerase-1 and p53 during EAE progression and following MSC treatment. Expression of the three brain MT isoforms increased significantly in EAE mice compared with healthy controls, but while expression of MT-1 and MT-3 increased along EAE course, MT-2 was up-regulated at the onset, but returned to levels similar to those of controls in chronic phase. The changes in the transcription and activity of the antioxidant enzymes and in expression of poly(ADP-ribose) polymerase-1 and p53 showed the same kinetics observed for MT-1 and MT-3 during EAE. Interestingly, i.v. administration of MSCs reduced the EAE-induced increases in levels/activities of all these proteins. These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult.

Intravenous Mesenchymal Stem Cells Improve Survival and Motor Function in Experimental Amyotrophic Lateral Sclerosis

“…Animals were sacrificed at d 125 ± 2, and glutathione S-transferase (GST) activity in spinal cord was measured as previously reported (18). Aliquots of pooled spinal cord samples from each experimental group were homogenized in 10 volumes (w/v) of ice-cold PBS (50 mmol/L, pH 7.8) and centrifuged at 700g for 5 min at 4°C.…”

Therapeutic Potential of Mesenchymal Stem Cells vs. Estradiol Benzoate or Avosoya on the Cerebellar Cortex of Ovariectomized Adult Albino Rats

“…MSCs exert their effects through their antioxidant properties. MSCs exhibited antioxidant activity through the effect on the levels of glutathione, and superoxide dismutase, and modulating the pathways of antioxidant-related protein activation [19,20]. Furthermore, Kim et al [21] suggested that early intravenous injection of MSCs after acute spinal cord injury may prevent further damage through enhancement of antioxidative mechanisms, without inducing adverse effects.…”

Mesenchymal Stem Cells Shape Microglia Effector Functions Through the Release of CX3CL1

“…Indeed MSC regulate effector functions of cells of the adaptive and innate immunity through the release of soluble factors such as prostaglandin E2 (PGE2), nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), and others [7] leading to the induction of peripheral tolerance [8]. Moreover, MSC can protect axons and improve neuronal survival [4,9,10] releasing antiapoptotic [11] or antioxidant molecules [12]. It has been also reported that MSC may foster endogenous neurogenesis [13] and oligodendrogenesis [14][15][16] not only by direct release of trophic factors but also by stimulating glial cells to secrete molecules leading to neuron survival and proliferation of the endogenous neural precursor cells [17].…”