ABSTRACT
The transplantation of mesenchymal stem cells (MSCs) proves to be useful to treat pathologies in which tissue damage is linked to oxidative stress (OS). The aim of our work was to evaluate whether primary human MSCs (hMSCs) can manage OS. For this, in vitro we assessed the following parameters: (1) cell viability of hMSCs exposed to increasing concentrations of reactive oxygen species (ROS; source: hydrogen peroxide), reactive nitrogen species (RNS; source: S-nitroso-N-acetylpenicillamine), or both (ROS and RNS; source: 3-morpholinosydnonimine hydrochloride); (2) intracellular level of reactive species in hMSCs exposed to ROS and RNS; (3) basal gene expression and activity of superoxide dismutases, catalase, and glutathione peroxidase of hMSCs; (4) basal level of total glutathione (GSx) of hMSCs; and (5) cell viability of GSx-depleted hMSCs exposed to ROS and/or RNS. Results showed that hMSCs have a high resistance to OS-induced death, which correlates with low levels of intracellular reactive species, constitutive expression of enzymes required to manage OS, and high levels of GSx. When hMSCs were depleted of GSx they lose their capacity to manage OS. Thus, in vitro hMSCs were able to scavenge ROS and RNS and efficiently manage OS. If this potential is maintained in vivo, hMSCs could also contribute to tissue regeneration, limiting OS-induced tissue damage.
Subject(s)
Mesenchymal Stem Cells/physiology , Oxidative Stress , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Catalase/genetics , Catalase/metabolism , Cell Line , Cell Survival , Fibroblasts , Gene Expression , Glutathione/metabolism , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Humans , Insulin-Secreting Cells , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolismABSTRACT
Animals selectively bred for a desirable trait retain wanted genes but exclude genes that may counteract the expression of the former. The possible interactions between selected and excluded genes cannot be readily studied in transgenic or knockout animals but may be addressed by crossing animals bred for opposite traits and studying the F2 offspring. Ninety-seven percent of Wistar-derived rats selectively bred for their voluntary low-alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh22 that encodes an enzyme with a low affinity for NAD+, whereas rats bred for high-alcohol consumption do not present the Aldh22 allele. This enzyme is inserted into mitochondria, where NADH-ubiquinone oxidoreductase (complex I) regenerates NAD+. The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investigated. Homozygous Aldh22/Aldh22 rats derived from a line of high-drinker F0 females (and low-drinker F0 males) showed a markedly higher ethanol consumption (3.9=/-0.5 g x kg(-1) x day(-1)) than homozygous animals derived from a line of low-drinker F0 females (and high-drinker F0 males) (1.8+/-0.4 g x kg(-1) x day(-1)). Mitochondria of F2 rats derived from high alcohol-consuming females were more active in oxidizing substrates that generate NADH for complex I than were mitochondria derived from low alcohol-consuming females, leading in the former to higher rates of acetaldehyde metabolism and to a reduced aversion to ethanol. This is the first demonstration that maternally derived genes can either allow or counteract the phenotypic expression of a mutated gene in the context of alcohol abuse or alcoholism
