Stress-induced Premature Senescence Program Activated in the Mesenchymal Stem Cells by Antioxidant Treatments

It is now well established that intracellular reactive oxygen species (ROS) mediate the regulation of many signaling cascades that define cell fate. The delicate balance between the production and elimination of ROS is essential for maintaining normal cell functions. Disruption of this balance caused by the antioxidant treatment can disturb various intracellular processes controlled by the systemic signaling. In the present study, we investigate the response of the mesenchymal stem cells (MSCs) to the sub-cytotoxic treatment with various antioxidants (tempol, NAC, resveratrol, DPI). We show that exposure of the proliferating MSC cultures to the antioxidants at concentrations which are widely used in the cell studies to protect cells from the oxidative stress, can cause replication stress and initiate the program of stress-induced preliminary senescence. We demonstrate that these effects can be explained by the disturbance of the ROS-depended degradation of the key proteins regulating DNA replication, e.g. cyclin A, Emi1, geminin. Our data show that enhanced intracellular elimination of ROS resulted from the pharmacologic manipulations can cause the antioxidant-induced damage of cells.