Abstract
Background: Treatment with mesenchymal stem cells (MSCs) has elicited considerable interest as an adjunctive therapy in sepsis. However, the encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis.Objectives: Here, we aimed to assess safety and efficacy of bone marrow-derived MSCs in a clinically relevant porcine model of progressive peritonitis-induced sepsis.Methods: Thirty-two anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned into four groups (n = 8 per group): (1) sham-operated group (CONTROL); (2) sham-operated group treated with MSCs (MSC-CONTROL); (3) sepsis group with standard supportive care (SEPSIS); and (4) sepsis group treated with MSCs (MSC-SEPSIS). Peritoneal sepsis was induced by inoculating cultivated autologous feces. MSCs (1 × 106/kg) were administered intravenously at 6 h after sepsis induction.Results: Before, 12, 18, and 24 h after the induction of peritonitis, we measured systemic, regional, and microvascular hemodynamics, multiple-organ functions, mitochondrial energy metabolism, systemic immune-inflammatory response, and oxidative stress. Administration of MSCs in the MSC-CONTROL group did not elicit any measurable acute effects. Treatment of septic animals with MSCs failed to mitigate sepsis-induced hemodynamic alterations or the gradual rise in Sepsis-related organ failure assessment scores. MSCs did not confer any protection against sepsis-mediated cellular myocardial depression and mitochondrial dysfunction. MSCs also failed to modulate the deregulated immune-inflammatory response.Conclusion: Intravenous administration of bone marrow-derived MSCs to healthy animals was well-tolerated. However, in this large-animal, clinically relevant peritonitis-induced sepsis model, MSCs were not capable of reversing any of the sepsis-induced disturbances in multiple biological, organ, and cellular systems.
Highlights
IntroductionEven though substantial progress has been made in understanding the underlying pathophysiology of sepsis, translation of these advances into clinically effective therapies has been disappointing
The lack of effective therapy for sepsis remains a major unmet medical need
We aimed to examine both the safety of mesenchymal stem cells (MSCs) in healthy animals and the effect of MSCs on various biological systems related to multiple pathophysiological pathways during sepsis progression
Summary
Even though substantial progress has been made in understanding the underlying pathophysiology of sepsis, translation of these advances into clinically effective therapies has been disappointing. No preclinical study published so far has demonstrated adverse effects associated with the application of MSCs in animal models of sepsis. It must be emphasized, that these encouraging results were largely derived from rodent models with clearly limited relevance to human sepsis. The encouraging effects of experiments with MSC in rodents have not been adequately studied in large-animal models with better relevance to human sepsis
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