Adaptive Redox Response of Mesenchymal Stromal Cells to Stimulation with Lipopolysaccharide Inflammagen: Mechanisms of Remodeling of Tissue Barriers in Sepsis

Abstract

Acute bacterial inflammation is accompanied by excessive release of bacterial toxins and production of reactive oxygen and nitrogen species (ROS and RNS), which ultimately results in redox stress. These factors can induce damage to components of tissue barriers, including damage to ubiquitous mesenchymal stromal cells (MSCs), and thus can exacerbate the septic multiple organ dysfunctions. The mechanisms employed by MSCs in order to survive these stress conditions are still poorly understood and require clarification. In this report, we demonstrated that in vitro treatment of MSCs with lipopolysaccharide (LPS) induced inflammatory responses, which included, but not limited to, upregulation of iNOS and release of RNS and ROS. These events triggered in MSCs a cascade of responses driving adaptive remodeling and resistance to a “self-inflicted” oxidative stress. Thus, while MSCs displayed high levels of constitutively present adaptogens, for example, HSP70 and mitochondrial Sirt3, treatment with LPS induced a number of adaptive responses that included induction and nuclear translocation of redox response elements such as NFkB, TRX1, Ref1, Nrf2, FoxO3a, HO1, and activation of autophagy and mitochondrial remodeling. We propose that the above prosurvival pathways activated in MSCs in vitro could be a part of adaptive responses employed by stromal cells under septic conditions.

Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis

“…However, the side effect of nitric oxide production in the cells was nitroxidative stress to the cellular constituents (shown below). Evidently, the stress‐adaptive mechanisms expressed under the above experimental conditions may allow the cells to avoid ‘self‐inflicted’ oxidative injury and activation of apoptosis as recently reported . In this light, the presence of high levels of constitutively expressed HSP70, which can suppress the processing of caspase 3 (Casp‐3, a marker of apoptosis), would explain a failure to detect activated Casp‐3 protein in the challenged cells (Fig.…”

Canine mesenchymal stem cells show antioxidant properties against thioacetamide‐induced liver injury in vitro and in vivo

“…showed that MSC treated with lipopolysaccharide, which induces inflammatory responses including release of ROS, induce a number of adaptive responses including induction and nuclear translocation of redox response elements such as nuclear factor‐κB and Nrf2. They suggested that the prosurvival pathways that are activated in MSC in vitro could be a part of an adaptive response employed by stromal cells under injury conditions …”

“…They suggested that the prosurvival pathways that are activated in MSC in vitro could be a part of an adaptive response employed by stromal cells under injury conditions. 65 A direct and specific effect of ROS in viability was ruled out using H2O2 and NAC in cultures. As expected, these molecules increased (H2O2) and decreased (NAC) intracellular ROS, but no direct relationship between viability and ROS levels was seen at the time points tested (data not shown).…”

The emerging antioxidant paradigm of mesenchymal stem cell therapy

“…Depletion of GSH results in a loss of tolerance to oxidative stress. MSCs also constitutively express heat‐shock protein 70 (HSP70) and sirtuin (SIRT)3, 18 which may also play a role in the resistance of MSCs to oxidative/nitrosative injury. SIRT1 is also required for MSC survival against H 2 O 2 and its overexpression has a protective effect 19 .…”