Mesenchymal Stromal/Stem Cells Enhance Bacterial Killing Partly Via Hemoxygenase-1 Expression in Macrophages from Healthy and Septic Patients and Accelerate Bacterial Clearance and Recovery in Preclinical Sepsis Model
CCCF ePoster library. Jerkic M. Nov 9, 2018; 233361
Dr. Mirjana Jerkic
Dr. Mirjana Jerkic
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Abstract
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Introduction & Objective: Sepsis, a syndrome of life-threatening organ dysfunction caused by dysregulated host response to infection (1, 2), is most commonly initiated by bacterial infection of the lung and abdominal cavity. Mesenchymal Stromal/Stem Cells (MSCs) have potent immunomodulatory properties, they demonstrated therapeutic potential in animal preclinical sepsis models (3, 4, 5) and are in early phase clinical trials for sepsis (6). We explored the role of hemoxygenase-1(HO-1) in mediating MSC-induced enhancement of Mɸ function in vitro and in a clinically relevant animal model of abdominal sepsis.



Methods: Blood monocytes, isolated from healthy donors and septic patients (in first 48h of sepsis) were differentiated into Mɸ and exposed to human umbilical cord (hUC) MSCs (obtained from Tissue Regeneration Therapeutics®, Toronto) in transwell plates for 48h. Mɸ phagocytosis was assessed using serum opsonized zymozan (SOZ) while their killing capabilities were tested using live E.coli. Protein expression was analyzed by Western blot. Mɸ were also isolated from peritoneal fluid (PLF) of septic rats challenged with cecal slurry (1g/kg, i.p.) 48h earlier, that been treated with UC-MSCs (10 mill/kg, i.v.) or placebo 4h after sepsis induction. Inflammation and bacterial clearance were assessed in PLF, BAL, and organs of the septic animals.



Results: Phagocytic efficacy and bacterial killing capacities were significantly increased in Mɸ from both healthy donors and septic patients co-cultured with UC-MSCs than in control Mɸ. Mɸ exposed to MSCs expressed more HO-1, an enzyme with anti-inflammatory and bactericidal properties. Peritoneal macrophages isolated from animals subjected to abdominal fecal demonstrated greater phagocytosis of SOZ when taken from UC-MSC treated vs. vehicle treated animals. Macrophages also expressed more HO-1. The direct HO-1 inducer Hemin increased macrophage phagocytosis from vehicle but not from UC-MSC treated animals. In contrast, the HO-1 antagonist ZnPP decreased phagocytosis in Mɸ from UC-MSC treated animals to the levels seen in macrophages from vehicle treated animals. The HO-1 increase in Mɸ was dependent on pro-resolvin mediators secreted by UC-MSCs, specifically PGE2 and Lipoxin A4. Septic animals cleared bacteria and recovered faster, if treated with UC-MSCs.



Conclusions: UC-MSCs are promising tool for sepsis treatment. UC-MSCs enhance macrophage phagocytosis and increase bacterial clearance, in part, via a mechanism involving UC-MSC induced HO-1 expression in macrophages. 


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