Extracellular DNA oxidation stimulates activation of NRF2 and reduces the production of ROS in human mesenchymal stem cells

Abstract

Introduction: Human blood normally contains circulating cell-free DNA (cirDNA). Cell-free DNA (cfDNA) present in cell culture medium is termed extracellular DNA (ecDNA). Its concentration, GC content and oxidation level depend on physiological state of the organism. cirDNA could probably be one of the aggressive factors encountered by therapeutic stem cells. The authors hypothesize that oxidized cirDNA could influence their survival rate. They aimed to uncover the effects of oxidized ecDNAs, including ecDNA of cultivated primary tumor cells and cirDNA from blood plasma of cancer patients on mesenchymal stem cells (MSCs).Areas covered: Increased concentrations of cfDNA stimulate a rapid increase in reactive oxygen species (ROS) synthesis and up-regulate antioxidant response genes (NRF2, KEAP1, SOD1, BRCA1, BCL2) in MSCs. This response is more prominent when cfDNA contains higher proportions of 8-oxo-dG. Within an hour, oxidized DNA induces a decrease in ROS production while NRF2 mRNA levels continue to augment and the NRF2 protein translocates into the nucleus. Additionally, oxidized DNA up-regulates PPRAG2 with no apparent induction of adipogenesis. This kind of response is specific for MSCs.Expert opinion: Oxidized cfDNA up-regulates NRF2 and PPARG2 and reduces ROS production in MSCs. These effects should be taken into account when considering therapeutic applications of stem cells.