Filho, MC Lourenço, Antunes, M.A., Braga, CL., Oliveira, TB., Kitoko, JZ., Castro, LL, Xisto, DG, Coelho, M S, Rocha, N, Martins, EG, de Carvalho, LRP, Galina, A, Weiss, DJ, Silva, JLapa e, Cruz, FF, and Rocco, PRM
Although bone marrow-derived mesenchymal stromal cells (BM-MSC) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSC 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 MSC from healthy and emphysematous donors (H-MSC and E-MSC) in vitro and to assess therapeutic potential of these MSC and their EV (H-EV and E-EV) in an in vivo model of severe emphysema. 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-MSC, E-MSC, H-EV or E-EV intravenously. In vitro characterization demonstrated that E-MSC present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β and HGF) and antioxidant (CAT, SOD, Nrf2 and GSH) genes and their EV had larger median diameter and lower average concentration. Compared to H-MSC, E-MSC mitochondria also exhibited higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSC and E-MSC induced an increase in iNOS and arginase-1 levels, but only H-MSC and their EV were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSC or E-EV demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, improved lung inflammation and morphometry, as well as reduced pulmonary arterial hypertension and right ventricular dysfunction induced by severe emphysema. Based on these results, we also compared naïve E-MSC and mitocepted E-MSC with H-MSC mitochondria (E-MSCMITO1:1), revealing that E-MSCMITO1:1 exhibited a higher respiration rate, an increase in gene expression of antioxidant mediators (CAT, SOD, Nrf2 and GSH-Px), mitofusin-2 and Miro1 (related to mitochondrial transfer) compared to naïve E-MSC. E-MSC and E-EV were unable to reverse cardiorespiratory dysfunction; however, E-MSC with mitochondrial reinforcement was found to have a more antioxidant profile and appears to benefit mitochondrial transfer more than naive E-MSC, suggesting a potential therapeutic approach that could potentiate the prognosis of autologous transplantation in severe COPD. [ABSTRACT FROM AUTHOR]