Genetically modified embryonic stem cells a tool to study the role of oxidative stress in cell death and differentiation

In physiologic concentrations, endogenous reactive oxygen species (ROS) help to maintain homeostasis. However, when ROS accumulate in excess for prolonged periods of time, they cause chronic oxidative stress and adverse effects. Oxidative stress is linked to the pathogenesis and pathobiochemistry of various diseases, including cancer, diabetes, cardiovascular and neurodegeneration. Organisms have evolved extensive enzymatic defense systems to protect against the deleterious effects of oxidants. The tripeptide glutathione (GSH) is part of these antioxidant systems that protect cells and tissues from oxidative damage. GSH is believed to function as an important cellular redox buffer and has been suggested to be involved in determining cell fate decisions, such as proliferation, differentiation and apoptosis. Mouse genetic models of disease are often limited by the inherent variability of animal experiments, the limited mouse life span, and the difficulties in manipulating whole animals. For instance, genetic rescue experiments and toxicological dose-response studies are impractical in whole animals. Furthermore, genetic cell models are more readily amenable to molecular dissection of disease mechanisms than are whole animals. Primary cultures or established cell lines are commonly used to analyse the cytotoxic effect of chemical factors, drugs and xenobiotics in vitro. An alternative approach will be provided by permanent lines of pluripotent embryonic stem (ES) cells, which are able to differentiate into specialized somatic cell types in vitro. ES cells carrying genetic mutations are a suitable system to study events occurring during development. In fact, during ES cell differentiation, tissue-specific genes, proteins, as well as functional properties are expressed in a developmentally regulated manner recapitulating processes of early embryonic development. In this review we report data showing the use of genetically modified ES-derived neurons, erythrocytes and cardiomyocytes in studying the role of oxidative stress in cell death and differentiation.