Mesenchymal Stem Cells in Sepsis and Associated Organ Dysfunction: A Promising Future or Blind Alley?

Abstract

Sepsis, newly defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is the most common cause of death in ICUs and one of the principal causes of death worldwide. Although substantial progress has been made in the understanding of fundamental mechanisms of sepsis, translation of these advances into clinically effective therapies has been disappointing. Given the extreme complexity of sepsis pathogenesis, the paradigm “one disease, one drug” is obviously flawed and combinations of multiple targets that involve early immunomodulation and cellular protection are needed. In this context, the immune-reprogramming properties of cell-based therapy using mesenchymal stem cells (MSC) represent an emerging therapeutic strategy in sepsis and associated organ dysfunction. This article provides an update of the current knowledge regarding MSC in preclinical models of sepsis and sepsis-induced acute kidney injury. Recommendations for further translational research in this field are discussed.

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

“…Given the extreme complexity of sepsis pathogenesis, the paradigm "one disease, one drug" is obviously flawed and combinations of multiple targets that involve early immunomodulation and cellular protection are needed. The immunomodulatory, anti-inflammatory, anti-apoptotic, metabolomic, and anti-microbial effects of mesenchymal stem cells (MSCs) may have scientific and clinical relevance in this context (1). Indeed, application of MSCs in preclinical models of sepsis has been associated with lower mortality, improved course of sepsis due to inhibition of pro-active elements of the immune system, and a change in the pro-and anti-cytokine ratio both in vitro and in vivo (1)(2)(3).…”

Mesenchymal stem cells have significant anti-infective effect on methicillin-resistant Staphylococcus epidermidis vascular graft infections

“…The antibacterial properties of MSCs are related with their immunomodulating and direct antibacterial effect on the infectious agent. [13,15,19,40] As immunomodulators, MSCs initiate a shift in the ratio of T helper cells through T helper 2 anti-inflammatory subtype and increase differentiation of naive T cells to regulatory phenotype. [13] They also modulate the activity of macrophages.…”

“…The direct anti-infectious effects are provided by secretion of antibacterial peptides and intensification of phagocytosis. [14,19] The increase in IL-1 and particularly its a subtype may be responsible from anti-infective properties of MSCs because it is well documented that IL-1a promotes the release of chemokines and adhesion molecules by inducing endothelial cells. [41,42] Thus, it provides white blood cells to reach the infected area with chemotaxis and augments inflammation.…”

“…In the literature, there are studies supporting these effects of experimental MSCs, many of which were performed on sepsis models. [19] Devaney et al [18] demonstrated in a mouse model of E. coli-induced pneumonia a lesser intensity of lung damage, lower bacterial load, and higher intensity of phagocytosis following the intratracheal administration of MSCs. Also, Pedrazza et al [21] showed a significant decrease in mortality in the group that received MSCs compared to the control group which was a mouse model of sepsis induced by the administration of E. coli into the peritoneal cavity.…”

“…[12,13] They also show direct antibacterial effect achieved by secretion of antibacterial peptides and augmentation of phagocytosis. [14] The efficacy of treatment with allogeneic and autogenic MSC transplantation has been demonstrated on myocardial infarction, [15] diabetes, [16] graft versus host disease, [17] acute infectious lung injury, [18] sepsis and organ dysfunction, [19] staphylococcus toxic shock syndrome, [20] and peritonitis. [21] Thus, the anti-infectious effect of MSCs may be studied on other clinically resistive forms of infection.…”