Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

Mirjana Jerkic; Claire Masterson; Lindsay Ormesher; Stéphane Gagnon; Sakshi Goyal; Razieh Rabani; Gail Otulakowski; Haibo Zhang; Brian P Kavanagh; John G Laffey

doi:10.3390/jcm8060847

Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

J Clin Med. 2019 Jun 13;8(6):847. doi: 10.3390/jcm8060847.

Authors

Mirjana Jerkic¹, Claire Masterson², Lindsay Ormesher³, Stéphane Gagnon⁴, Sakshi Goyal⁵, Razieh Rabani⁶, Gail Otulakowski⁷, Haibo Zhang³, Brian P Kavanagh^{8

9}, John G Laffey^{10

11

12}

Affiliations

¹ St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada. jerkicm@smh.ca.
² Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway H91 TK33, Ireland. claire.masterson@nuigalway.ie.
³ St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada. lormeshe@mail.uoguelph.ca.
⁴ St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada. GagnonS@smh.ca.
⁵ St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada. sakshigoyal383@gmail.com.
⁶ St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada. Razieh.Rabani@utoronto.ca.
⁷ Department of Critical Care Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Gail.Otulakowski@sickkids.ca.
⁸ Department of Critical Care Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Brian.Kavanagh@sickkids.ca.
⁹ Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, ON M5G 1E2, Canada. Brian.Kavanagh@sickkids.ca.
¹⁰ Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway H91 TK33, Ireland. john.laffey@nuigalway.ie.
¹¹ Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, ON M5G 1E2, Canada. john.laffey@nuigalway.ie.
¹² Anaesthesia, School of Medicine, National University of Ireland, Galway, H91 TK33, Ireland. john.laffey@nuigalway.ie.

Abstract

Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0-3.0) × 10⁹ Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naïve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 × 10⁷ cells/kg). Lung injury severity, cellular infiltration, and E. coli colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and naïve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs-but not naïve UC-MSCs-significantly decreased the alveolar arterial gradient (455 93 and 520 81, mmHg, respectively) compared to that of vehicle animals (544 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naïve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naïve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naïve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in E. coli pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS).

Keywords: macrophage; mesenchymal stromal cell; phagocytosis; pneumonia; sepsis.

Abstract

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