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).
Highlights
Mesenchymal stromal cells (MSCs) represent a promising therapeutic strategy for sepsis [1] and for acute respiratory distress syndrome (ARDS) [2]
We hypothesized that IL-10 overexpressing umbilical-cord-derived MSCs (UC-MSCs) would more effectively attenuate E. coli-induced lung injury compared to naïve UC-MSCs
Our demonstration that IL-10 overexpression in UC-MSCs can enhance their therapeutic effects in a clinically relevant infection model and can enhance human macrophage function via this mechanism suggests that this approach deserves further exploration as a potential therapy for infection-induced ARDS
Summary
Mesenchymal stromal cells (MSCs) represent a promising therapeutic strategy for sepsis [1] and for acute respiratory distress syndrome (ARDS) [2]. MSCs are multipotent adult stromal cells with the capacity to differentiate into several cell types and are present in multiple tissues, including the bone marrow, adipose tissue, and umbilical cord They are found in the perivascular space in several tissues, including the umbilical cord, which is an accessible biologic waste product that generates high amounts of MSCs. We recently demonstrated that human umbilical-cord-derived MSCs (UC-MSCs) attenuate Escherichia coli (E. coli)-induced acute lung injury [3]. Prior studies of overexpression of IL-10 in MSCs has demonstrated enhanced MSC therapeutic efficacy in preclinical models of endotoxin-induced [13] and ischemia–reperfusion-induced [14] lung injury and following myocardial infarction [15]. We further hypothesized that this effect would be mediated in part via enhanced macrophage phagocytosis and killing of E. coli bacteria
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