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Trialing Mesenchymal Stem Cell Therapy as an Effective Approach for Sepsis Treatment

Review of “Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial” from STEM CELLS by Stuart P. Atkinson 

Arising as a life-threating complication of infection, the pathogenesis of sepsis involves a sustained inflammatory response with associated tissue damage and immune suppression [1, 2]. While this often-fatal condition currently lacks adequate therapeutic approaches that may drive improvement in patient outcomes [3], the emergence of mesenchymal stem cell (MSC) therapy [4] has provided some hope to the multitude of patients worldwide, given the innate capacity of MSCs to modulate host immune responses and their low inherent immunogenicity.

Researchers from the laboratory of Desirée Perlee (University of Amsterdam, The Netherlands) sought to develop a new and efficient MSC-based therapy to fight sepsis, and their new study in STEM CELLS sought to evaluate the effect of intravenous infusion of allogeneic adipose-derived MSCs (ASCs) on early inflammatory responses in a randomized, single-blind, parallel group, placebo-controlled trial [5]. To do this, the authors employed a well-characterized model of human inflammation: the intravenous injection of purified lipopolysaccharide (LPS - a component of the outer membrane of Gram-negative bacteria) into healthy human subjects [6]. 

Here are the details of this exciting new trial:

  • Four sepsis treatment arms covered the 32 healthy male subjects enrolled
    • each subject received intravenous LPS one hour after the infusion of one of three different concentrations of ASCs (a quarter of a million, one million, or four million cells per kilogram) or a placebo control injection
    • ASCs failed to produce any serious unwanted side effects suggesting both tolerance and safety, but displayed no significant influence on neutrophil responses, suggesting that ASCs do not attenuate neutrophil-mediated damage
  • While LPS induced a fever after 2-3 hours, only the highest dose of ASCs increased the febrile response
    • LPS also induced tachycardia and transient flu-like symptoms, although ASC infusions did not influence these symptoms at any concentration
  • High-dose ASCs exerted mixed pro‐inflammatory (enhanced IL-8 release) and anti‐inflammatory effects (trend to reduce IL-12p40 and increased IL-10 and TFG-β release), enhanced coagulation activation (possibly tissue factor-dependent), and a “blunted” fibrinolytic response
    • Blood analysis indicated an initial increase in innate immune pathway-associated gene expression at two hours, followed by a decrease at four hours after LPS administration suggesting that the high-dose ASC infusion influences blood leukocyte host responses
  • ASC infusion did not modify the lost responsiveness of leukocytes to various bacterial agonists observed in sepsis

The authors highlight their trial as the first to report on MSC therapy in a well-established model of systemic inflammation, and they now aim to undertake further testing in sepsis patients to assess safety and efficacy, to understand the effects on the host response during sepsis, and to delineate mechanisms of action.

For more on MSC therapy and more new approaches for the sepsis treatment, stay tuned to the Stem Cells Portal!

 

References

  1. Delano MJ and Ward PA, The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev 2016;274:330-353.
  2. van der Poll T, van de Veerdonk FL, Scicluna BP, et al., The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 2017;17:407-420.
  3. Angus DC and van der Poll T, Severe sepsis and septic shock. N Engl J Med 2013;369:2063.
  4. Ho MS, Mei SH, and Stewart DJ, The Immunomodulatory and Therapeutic Effects of Mesenchymal Stromal Cells for Acute Lung Injury and Sepsis. J Cell Physiol 2015;230:2606-17.
  5. Perlee D, van Vught LA, Scicluna BP, et al., Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial. STEM CELLS 2018;36:1778-1788.
  6. Suffredini AF and Noveck RJ, Human endotoxin administration as an experimental model in drug development. Clin Pharmacol Ther 2014;96:418-22.