Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

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.

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

“…Of concern is that clinical observational studies have found that the Cat gene is associated with pathophysiological processes in pulmonary vascular disease mediated by oxidative stress and is significantly downregulated in the development of emphysema, as well as in PAH and chronic thromboembolic pulmonary hypertension (CTEPH). At the same time, high expression of CAT is an essential factor in the prognosis of patients with pulmonary hypertension [ 76 , 77 ]. Interestingly, the prediction result showed that the down mitochondrial-related genes such as Cat with the most regulations could be targeted and regulated by 26 miRNAs.…”

RGD-Hydrogel Improves the Therapeutic Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Phosgene-Induced Acute Lung Injury in Rats

“…MSCs have been reported to reduce inflammation severity and regulate endothelial permeability by releasing anti-inflammatory cytokines and growth factors [ 24 ]. However, MSCs entering the injured lung via intravenous or intratracheal infusion initially suffer severe cell death due to the pulmonary first-pass effect and harsh microenvironment, minimising the therapeutic effects [ 25 ]. The success of MSCs therapies depends heavily on the cell survival, engraftment, and the appropriate delivery systems that can match desired therapeutic applications [ 16 ].…”

MitoEVs: A new player in multiple disease pathology and treatment

“…To date, mitoEVs from healthy cells (mainly stem cells) have been shown to play therapeutic roles in lung injury models by regulating the metabolic state and phenotypes of immune cells. For example, MSC‐derived EVs (MSC‐EVs) delivered mitochondria to improve the oxygen consumption rate (OCR) and mtDNA and ATP levels in alveolar macrophages (AMs) in vitro (Antunes et al., 2021 ; Xia et al., 2022 ). In LPS‐induced ALI mice, MSC‐EVs can deliver mitochondria to the alveolar epithelium, thereby restoring ATP production and reducing bronchoalveolar lavage leukocytosis and lung inflammation (Islam et al., 2012 ; Xia et al., 2022 ).…”