Oxidative stress response of mouse bone marrow mesenchymal stem cells to stimulation with lipopolysaccharides

Sepsis is a serious complication of wounds, burns, radiation exposure, and combinations thereof, and is a major cause of morbidity and mortality. Bacterial toxins, such as lipopolysaccharides (LPS), cause systemic inflammation and oxidative stress, which damages sensitive tissues. Effect of LPS is mediated by the toll‐like receptor 4 signaling cascade, leading to transcriptional activation of NF‐κB target genes, such as inducible nitric oxide synthase (iNOS) and heme oxygenase 1 (HO1) that are essential for cellular redox regulation. Since stem cell therapy is a promising treatment for traumatic injury and sepsis, we explored the response of mouse bone marrow mesenchymal stem cells (mBMSCs), isolated from B6D2F1/J female mice, to LPS. Using fluoresecent imaging, qPCR, and immunoblot techniques, we demonstrated that treatment of mBMSCs with 5 – 500 ng/ml LPS resulted in increases in nuclear translocation of thioredoxin and NF‐κB(p65) followed by up‐regulation of gene and protein expression of iNOS and HO1, and NO production. LPS‐induced up‐regulation of the iNOS pathway occurred without causing apoptosis or down‐regulation of mBMSC proliferation. We suggest that induction of the antioxidant enzyme HO1 after LPS treatment could be a part of compensatory response maintaining redox homeostasis and protecting mBMSCs from detrimental effects of overexpressed iNOS. (Supported by NIH/NIAID YI‐AI‐5045‐04).