Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

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 × 10 6 /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. Horak et al. Stem Cell Therapy for Sepsis 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.

Mesenchymal stromal cells for sepsis and septic shock: Lessons for treatment of COVID-19

“…Although our work has shown that MSCs are effective in murine and swine septic shock models, improving survival, organ failure, and bacterial load, we did not observe any MSC impact on inflammatory secreted factors, unlike other studies 28,30 . Similarly, in a porcine sepsis model, Horak et al did not find any impact of BM‐MSCs on inflammation 31 . However, they did not observe either any beneficial effect of MSCs on organ failures, unlike us.…”

“…28,30 Similarly, in a porcine sepsis model, Horak et al did not find any impact of BM-MSCs on inflammation. 31 However, they did not observe either any beneficial effect of MSCs on organ failures, unlike us. Despite the report of contradictory results, a recent metaanalysis of 29 animal studies, including 1266 animals, demonstrated that MSC therapy was related to a significant lower mortality rate.…”

Efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies

“…Regarding the safety and effectiveness of MSCs in the treatment of sepsis, phase 1 clinical trials have been conducted [43,44], but MSCs have not yet been used for the clinical treatment of sepsis. To our knowledge, a recent large-animal study [50], using the animal models of pigs, demonstrated that MSCs were not capable of reducing the mortality induced by sepsis. Concerning its small sample size, more large-animal studies are needed.…”

Efficacy of mesenchymal stem cell therapy for sepsis: A meta-analysis of preclinical studies

“…Regarding the safety and effectiveness of MSCs in the treatment of sepsis, phase 1 clinical trials have been conducted [43,44], but MSCs have not yet been used for the clinical treatment of sepsis. To our knowledge, a recent large-animal study [53], using the animal models of pigs, demonstrated that MSCs were not capable of reducing the mortality induced by sepsis. Concerning its small sample size, more large-animal studies are needed.…”