• Mirjana Jerkic, Stéphane Gagnon, Razieh Rabani, Taylor Ward-Able, Claire Masterson, Gail Otulakowski, Gerard F Curley, John Marshall, Brian P Kavanagh, and John G Laffey.
• From the Keenan Research Centre for Biomedical Science, St. Michael's Hospital (M.J., S.G., R.R., T.W.-A., C.M., G.F.C., J.M., J.G.L.) Departments of Surgery and Interdepartmental Division of Critical Care (J.M.) Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care (B.P.K., J.G.L.), University of Toronto, Toronto, Canada Regenerative Medicine Institute at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland (C.M., J.G.L.) Translational Medicine (G.O.) Department of Critical Care Medicine (B.P.K.), Hospital for Sick Children, Toronto, Canada Departments of Anesthesia and Critical Care Medicine, St. Michael's Hospital, Toronto, Canada (G.F.C., J.G.L.) Department of Anesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland (G.F.C.).
• Anesthesiology. 2020 Jan 1; 132 (1): 140-154.

BackgroundMesenchymal stromal cells have therapeutic potential in sepsis, but the mechanism of action is unclear. We tested the effects, dose-response, and mechanisms of action of cryopreserved, xenogeneic-free human umbilical cord mesenchymal stromal cells in a rat model of fecal peritonitis, and examined the role of heme oxygenase-1 in protection.MethodsSeparate in vivo experiments evaluated mesenchymal stromal cells in fecal sepsis, established dose response (2, 5, and 10 million cells/kg), and the role of heme oxygenase-1 in mediating human umbilical cord-derived mesenchymal stromal/stem cell effects. Ex vivo studies utilized pharmacologic blockers and small inhibitory RNAs to evaluate mechanisms of mesenchymal stromal cell enhanced function in (rodent, healthy and septic human) macrophages.ResultsHuman umbilical cord mesenchymal stromal cells reduced injury and increased survival (from 48%, 12 of 25 to 88%, 14 of 16, P = 0.0033) in fecal sepsis, with dose response studies demonstrating that 10 million cells/kg was the most effective dose. Mesenchymal stromal cells reduced bacterial load and peritoneal leukocyte infiltration (from 9.9 ± 3.1 × 10/ml to 6.2 ± 1.8 × 10/ml, N = 8 to 10 per group, P < 0.0001), and increased heme oxygenase-1 expression in peritoneal macrophages, liver, and spleen. Heme oxygenase-1 blockade abolished the effects of mesenchymal stromal cells (N = 7 or 8 per group). Mesenchymal stromal cells also increased heme oxygenase-1 expression in macrophages from healthy donors and septic patients. Direct ex vivo upregulation of macrophage heme oxygenase-1 enhanced macrophage function (phagocytosis, reactive oxygen species production, bacterial killing). Blockade of lipoxin A4 production in mesenchymal stromal cells, and of prostaglandin E2 synthesis in mesenchymal stromal cell/macrophage cocultures, prevented upregulation of heme oxygenase-1 in macrophages (from 9.6 ± 5.5-fold to 2.3 ± 1.3 and 2.4 ± 2.3 respectively, P = 0.004). Knockdown of heme oxygenase-1 production in macrophages ablated mesenchymal stromal cell enhancement of macrophage phagocytosis.ConclusionsHuman umbilical cord mesenchymal stromal cells attenuate systemic sepsis by enhancing peritoneal macrophage bacterial killing, mediated partly via upregulation of peritoneal macrophage heme oxygenase-1. Lipoxin A4 and prostaglandin E2 play key roles in the mesenchymal stromal cell and macrophage interaction.

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