Critical Care Medicine  |   January 2020
Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats
Author Notes
  • 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.), and 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.), and 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.); and Department of Anesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland (G.F.C.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Data from this manuscript were presented at the American Thoracic Society Annual Scientific Meetings that took place May 19-24, 2017, in Washington, D.C., and May 18-23, 2018, in San Diego, California.
    Data from this manuscript were presented at the American Thoracic Society Annual Scientific Meetings that took place May 19-24, 2017, in Washington, D.C., and May 18-23, 2018, in San Diego, California.×
  • Submitted for publication January 14, 2019. Accepted for publication September 16, 2019.
    Submitted for publication January 14, 2019. Accepted for publication September 16, 2019.×
  • Deceased.
    Deceased.×
  • Address correspondence to Dr. Laffey: Anaesthesia and Intensive Care Medicine, School of Medicine, National University of Ireland Galway, Galway, Ireland. john.laffey@nuigalway.ie. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Gastrointestinal and Hepatic Systems / Obstetric Anesthesia
Critical Care Medicine   |   January 2020
Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats
Anesthesiology 1 2020, Vol.132, 140-154. doi:https://doi.org/10.1097/ALN.0000000000003018
Anesthesiology 1 2020, Vol.132, 140-154. doi:https://doi.org/10.1097/ALN.0000000000003018
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Sepsis is a syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection for which there is no direct treatment

  • Mesenchymal stromal cells have potent immunomodulatory, proreparative, and regenerative properties and have potential as therapeutics for sepsis

  • Mesenchymal stromal cells enhance bacterial killing by augmenting macrophage function

What This Article Tells Us That Is New:

  • In a rat model of fecal peritonitis, human umbilical cord mesenchymal stromal cells improved survival and reduced bacterial load by enhancing peritoneal macrophage function partly through induction of macrophage heme oxygenase-1

  • Lipoxin A4 and prostaglandin E2 were found to play important roles in mediating the effect of human umbilical cord mesenchymal stromal cells on peritoneal macrophage heme oxygenase-1 expression

Background: Mesenchymal 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.

Methods: Separate 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.

Results: Human 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 × 106/ml to 6.2 ± 1.8 × 106/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.

Conclusions: Human 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.