Critical Care Medicine  |   May 2019
Extracellular Vesicles from Interferon-γ–primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli–induced Acute Lung Injury in Rats
Author Notes
  • From the Keenan Research Centre for Biomedical Science (A.K.V., M.J., L.O., S. Gagnon, S. Goyal, R.R., C.M., C.S., C.C.d.S., G.F.C., J.G.L.), Interdepartmental Division of Critical Care Medicine and Department of Critical Care (C.C.d.S., G.F.C., J.G.L.), and Department of Anesthesia (G.F.C., J.G.L.), St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Chemical Engineering and Applied Chemistry (F.X.G.), University of Toronto, Toronto, Ontario, Canada; Department of Chemical Engineering, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario, Canada (P.Z.C., F.X.G.); Department of Anesthesia, Royal College of Surgeons in Ireland, Dublin, Ireland (G.F.C.); Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland (J.G.L.).
  • Submitted for publication July 16, 2018. Accepted for publication January 10, 2019.
    Submitted for publication July 16, 2018. Accepted for publication January 10, 2019.×
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • This article is accompanied by an editorial on p. 683.
    This article is accompanied by an editorial on p. 683.×
  • This article has a video abstract.
    This article has a video abstract.×
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    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).×
  • Address correspondence to Dr. Laffey: Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, 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 / Infectious Disease / Obstetric Anesthesia / Respiratory System
Critical Care Medicine   |   May 2019
Extracellular Vesicles from Interferon-γ–primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli–induced Acute Lung Injury in Rats
Anesthesiology 5 2019, Vol.130, 778-790. doi:10.1097/ALN.0000000000002655
Anesthesiology 5 2019, Vol.130, 778-790. doi:10.1097/ALN.0000000000002655
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Mesenchymal stromal cells are multipotent adult stem cells with the capacity to differentiate into multiple cell types and have immunomodulatory properties that have been shown to have substantial therapeutic promise in preclinical acute lung injury models

  • Mesenchymal stromal cells release extracellular vesicles, which are small, spherical membrane fragments comprising distinct populations including both exosomes and microvesicles, which have therapeutic effects in several disease models

  • Mesenchymal stromal cells are activated or primed by the injury microenvironment, which may be replicated by prior activation of the mesenchymal stromal cells

What This Article Tells Us That Is New:

  • In a rat model of Escherichia coli–induced pneumonia, extracellular vesicles derived from human umbilical cord mesenchymal stromal cells primed with interferon-γ more effectively attenuated E. coli–induced lung injury than did extracellular vesicles from naïve mesenchymal stromal cells, possibly by enhanced macrophage phagocytosis and killing of E. coli bacteria

Background: Human umbilical cord mesenchymal stromal cells possess considerable therapeutic promise for acute respiratory distress syndrome. Umbilical cord mesenchymal stromal cells may exert therapeutic effects via extracellular vesicles, while priming umbilical cord mesenchymal stromal cells may further enhance their effect. The authors investigated whether interferon-γ–primed umbilical cord mesenchymal stromal cells would generate mesenchymal stromal cell–derived extracellular vesicles with enhanced effects in Escherichia coli (E. coli) pneumonia.

Methods: In a university laboratory, anesthetized adult male Sprague–Dawley rats (n = 8 to 18 per group) underwent intrapulmonary E. coli instillation (5 × 109 colony forming units per kilogram), and were randomized to receive (a) primed mesenchymal stromal cell–derived extracellular vesicles, (b) naïve mesenchymal stromal cell–derived extracellular vesicles (both 100 million mesenchymal stromal cell–derived extracellular vesicles per kilogram), or (c) vehicle. Injury severity and bacterial load were assessed at 48 h. In vitro studies assessed the potential for primed and naïve mesenchymal stromal cell–derived extracellular vesicles to enhance macrophage bacterial phagocytosis and killing.

Results: Survival increased with primed (10 of 11 [91%]) and naïve (8 of 8 [100%]) mesenchymal stromal cell–derived extracellular vesicles compared with vehicle (12 of 18 [66.7%], P = 0.038). Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles reduced alveolar–arterial oxygen gradient (422 ± 104, 536 ± 58, 523 ± 68 mm Hg, respectively; P = 0.008), reduced alveolar protein leak (0.7 ± 0.3, 1.4 ± 0.4, 1.5 ± 0.7 mg/ml, respectively; P = 0.003), increased lung mononuclear phagocytes (23.2 ± 6.3, 21.7 ± 5, 16.7 ± 5 respectively; P = 0.025), and reduced alveolar tumor necrosis factor alpha concentrations (29 ± 14.5, 35 ± 12.3, 47.2 ± 6.3 pg/ml, respectively; P = 0.026) compared with vehicle. Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles enhanced endothelial nitric oxide synthase production in the injured lung (endothelial nitric oxide synthase/β-actin = 0.77 ± 0.34, 0.25 ± 0.29, 0.21 ± 0.33, respectively; P = 0.005). Both primed and naïve mesenchymal stromal cell–derived extracellular vesicles enhanced E. coli phagocytosis and bacterial killing in human acute monocytic leukemia cell line (THP-1) in vitro (36.9 ± 4, 13.3 ± 8, 0.1 ± 0.01%, respectively; P = 0.0004) compared with vehicle.

Conclusions: Extracellular vesicles from interferon-γ–primed human umbilical cord mesenchymal stromal cells more effectively attenuated E. coli–induced lung injury compared with extracellular vesicles from naïve mesenchymal stromal cells, potentially via enhanced macrophage phagocytosis and killing of E. coli.