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Effect of Preconditioned Mesenchymal Stromal Cells on Early Microvascular Disturbance in a Mouse Sepsis Model
Nathalie Baudry1, Julie Starck1,2, Clotilde Aussel3
1Laboratoire d'Etude de la Microcirculation, Université Paris VII Lariboisière St-Louis, UMR 942, Paris, France.
Abstract:
Septic patients often die in a context of multiple organ dysfunction syndrome (MODS), despite the macro-hemodynamic parameters being normalized and after the onset of antibiotic therapy. Microcirculation injury during sepsis affects capillary permeability and leukocyte-endothelium interactions and is thought to be instrumental in organ injury. Several studies have demonstrated a beneficial effect of mesenchymal stromal cells (MSCs) injection on survival and organ dysfunctions in sepsis models. In vivo activity of MSCs also appears to be very much dependent on the information provided before injection. Indeed preconditioning by interferon γ (IFNγ; MSC-IFNγ) increases immunosuppressive capacity of MSCs in vitro and in vivo. Therefore, the objective was to evaluate the effect of MSC naive or IFNγ preconditioned on leukocyte-endothelium interactions in a polymicrobial sepsis model by intraperitoneal feces injection. Six hours (H6) after this induction, we used intravital microscopy in mice cremaster muscle venules to study the flow behavior of leukocytes. Plasmas were harvested to evaluate inflammation level and endothelial activation. We showed that MSC-IFNγ have a beneficial effect on microcirculation, by increasing the flow of white blood cells (WBCs) and the percentage of venules containing flowing WBCs, by significantly reducing the adhesion of WBCs and by increasing the average red blood cell velocity (VRBC). In conclusion, our results suggest that intravenous injection of preconditioned MSC-IFNγ improves microvascular hemodynamics in early phases of sepsis.
Insights
Preconditioning mesenchymal stromal cells (MSCs) with interferon gamma (IFNγ) improved microcirculation in a mouse sepsis model. This therapy enhanced white blood cell flow and red blood cell velocity, aiding early sepsis recovery.
Area of Science:
- Biomedical Engineering
- Immunology
- Critical Care Medicine
Background:
- Sepsis often leads to multiple organ dysfunction syndrome (MODS) despite treatment, with microcirculation injury being a key factor.
- Mesenchymal stromal cells (MSCs) show promise in sepsis models, with their efficacy potentially enhanced by preconditioning.
- Interferon gamma (IFNγ) preconditioning of MSCs (MSC-IFNγ) boosts their immunosuppressive capabilities.
Purpose of the Study:
- To investigate the impact of naive versus IFNγ-preconditioned MSCs on leukocyte-endothelium interactions in a polymicrobial sepsis model.
- To assess the therapeutic effects of MSC-IFNγ on microvascular hemodynamics during early sepsis.
Main Methods:
- A polymicrobial sepsis model was induced in mice via intraperitoneal feces injection.
- Intravital microscopy of cremaster muscle venules was used to analyze leukocyte behavior at 6 hours post-induction.
- Plasma analysis was performed to evaluate inflammation and endothelial activation markers.
Main Results:
- MSC-IFNγ treatment significantly improved white blood cell (WBC) flow and increased the percentage of venules with flowing WBCs.
- A notable reduction in WBC adhesion and an increase in average red blood cell velocity (VRBC) were observed in the MSC-IFNγ group.
- MSC-IFNγ demonstrated a beneficial effect on microcirculation compared to naive MSCs or control.
Conclusions:
- Intravenous administration of IFNγ-preconditioned MSCs effectively improves microvascular hemodynamics in the early stages of sepsis.
- MSC-IFNγ therapy mitigates leukocyte-endothelium interactions, suggesting a potential therapeutic strategy for sepsis-induced organ injury.
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