Abstract
Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.
Highlights
Chronic obstructive pulmonary disease (COPD) is among the three leading causes of death worldwide, claiming over 3 million lives annually (Global Initiative for Chronic Obstructive Lung Diseases [GOLD], 2020)
We have previously demonstrated that systemic administration of BM-Mesenchymal stromal cell (MSC) reduced lung inflammation and damage and induced macrophage polarization to an anti-inflammatory M2 profile in moderate experimental emphysema induced by elastase (Antunes et al, 2014)
By using a multiple-dose protocol of elastase-induced emphysema that resembles advanced human emphysema, which has been extensively characterized in our laboratory (Antunes et al, 2014; Padilha et al, 2015; Henriques et al, 2016; Oliveira et al, 2016; Poggio et al, 2018), we demonstrated that E-MSCs and E-extracellular vesicles (EVs) did not yield the same therapeutic benefits as those of H-MSCs and H-EVs
Summary
Chronic obstructive pulmonary disease (COPD) is among the three leading causes of death worldwide, claiming over 3 million lives annually (Global Initiative for Chronic Obstructive Lung Diseases [GOLD], 2020). Mesenchymal stromal cell (MSC) therapy has demonstrated immunomodulatory and regenerative actions in experimental models of lung diseases by secreting soluble trophic factors and extracellular vesicles (EVs) and by transferring their mitochondria via tunneling nanotubes (Islam et al, 2012; Guan et al, 2013; Antunes et al, 2014; Jackson et al, 2016; Morrison et al, 2017; Poggio et al, 2018; Lopes-Pacheco et al, 2020) Both EVs and mitochondrial transfer were able to induce protective and antimicrobial actions, recover alveolar bioenergetics, and enhance macrophage phagocytic capacity in in vitro and in vivo models of acute respiratory distress syndrome (Islam et al, 2012; Jackson et al, 2016; Morrison et al, 2017). Despite demonstrating safety, efficacy was not clearly demonstrated in individuals with moderate to severe COPD in early stage clinical trials (Weiss et al, 2013; Stolk et al, 2016), suggesting that MSC-based approaches still need to be better understood and optimized to achieve success in clinical practice
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