Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.
BACKGROUND
Sepsis refers to the clinical syndrome of severe systemic inflammation precipitated by infection. Despite appropriate antimicrobial therapy, sepsis-related morbidity and mortality remain intractable problems in critically ill patients. Moreover, there is no specific treatment strategy for the syndrome of sepsis-induced multiple organ dysfunction.


OBJECTIVE
We hypothesized that mesenchymal stem cells (MSCs), which have been shown to have immunomodulatory properties, would reduce sepsis-induced inflammation and improve survival in a polymicrobial model of sepsis.


METHODS
Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of MSCs or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage fluid and tissues were collected for analyses. Longer-term studies were performed with antibiotic coadministration to assess the effect of MSCs on survival.


RESULTS
MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs alone reduced systemic and pulmonary cytokine levels in mice with CLP-induced sepsis, preventing acute lung injury and organ dysfunction, despite the low levels of cell persistence. Microarray data highlighted an overall down-regulation of inflammation and inflammation-related genes (such as IL-10, IL-6) and a shift toward up-regulation of genes involved in promoting phagocytosis and bacterial killing. Finally, bacterial clearance was significantly greater in MSC-treated mice, in part due to enhanced phagocytotic activity of the host immune cells.


CONCLUSIONS
These data demonstrate that MSCs have beneficial effects on experimental sepsis, possibly by paracrine mechanisms, and suggest that immunomodulatory cell therapy may be an effective adjunctive treatment to reduce sepsis-related morbidity and mortality.
Mei
Shirley H J
SH
The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada, K1H 8L6.
Haitsma
Jack J
JJ
Dos Santos
Claudia C
CC
Deng
Yupu
Y
Lai
Patrick F H
PF
Slutsky
Arthur S
AS
Liles
W Conrad
WC
Stewart
Duncan J
DJ
D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005260:Female; D005786:Gene Expression Regulation; D056747:Immunomodulation; D007249:Inflammation / Q000235:genetics / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis
D000900:Anti-Bacterial Agents