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

Mariana A Antunes, Cassia L Braga, Tainá B Oliveira, Jamil Z Kitoko, Ligia L Castro, Debora G Xisto, Mariana S Coelho, Nazareth Rocha, Rodrigo P Silva-Aguiar, Celso Caruso-Neves, Eduarda G Martins, Clara Fernandes Carvalho, Antônio Galina, Daniel J Weiss, José R Lapa E Silva, Miquéias Lopes-Pacheco, Fernanda F Cruz, Patricia R M Rocco, Mariana A Antunes, Cassia L Braga, Tainá B Oliveira, Jamil Z Kitoko, Ligia L Castro, Debora G Xisto, Mariana S Coelho, Nazareth Rocha, Rodrigo P Silva-Aguiar, Celso Caruso-Neves, Eduarda G Martins, Clara Fernandes Carvalho, Antônio Galina, Daniel J Weiss, José R Lapa E Silva, Miquéias Lopes-Pacheco, Fernanda F Cruz, Patricia R M Rocco

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.

Keywords: COPD; cell therapy; extracellular vesicles; inflammation; macrophages; mesenchymal stromal cells; mitochondria.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Antunes, Braga, Oliveira, Kitoko, Castro, Xisto, Coelho, Rocha, Silva-Aguiar, Caruso-Neves, Martins, Carvalho, Galina, Weiss, Lapa e Silva, Lopes-Pacheco, Cruz and Rocco.

Figures

FIGURE 1
FIGURE 1
Charaterization of mediators produced by MSCs from healthy and emphysematous donors. H-MSCs, bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from healthy donors; E-MSCs, BM-MSCs obtained from emphysematous donors. Gene expression profile of tumor necrosis factor α-induced protein-6 (TSG-6), indoleamine 2,3-dioxygenase 1 (IDO-1), interleukin-1 receptor antagonist (IL-1RN), interleukin 10 (IL-10), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and hepatocyte growth factor (HGF) in H-MSCs and E-MSCs. Data are expressed as means ± standard deviation of 5–6 samples in each group. *P < 0.05 vs. the H-MSC group.
FIGURE 2
FIGURE 2
Characterization of EVs secreted by MSCs from healthy and emphysematous donors. H-MSCs, bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from healthy donor; E-MSCs, BM-MSCs obtained from emphysematous donors; H-EVs, extracellular vesicles derived from BM-MSCs obtained from healthy donors; E-EVs, extracellular vesicles derived from BM-MSCs obtained from emphysematous donors. (A) Representative scanning electron microscopy of H-MSCs and E-MSCs, illustrating EV release from the surface of both types of MSCs. (B–D) Characterization of H-EVs and E-EVs, as determined by total protein content (B) and the size (C), concentration (D), and distribution (E) of secreted particles, measured by the Bradford assay and nanoparticle tracking analysis, respectively. Data are expressed as medians (interquartile range) of 5–6 samples in each group. *P < 0.05 vs. the H-EV group.
FIGURE 3
FIGURE 3
Characterization of mitochondria of MSCs from healthy and emphysematous donors. (A) An OROBOROS system was used to measure basal (Routine), spare respiration capacity (SPC) and maximum (electron transfer system, ETS) mitochondrial respiration in H-MSCs and E-MSCs. (B) Citrate synthase was used as a quantitative enzyme marker for the presence of intact mitochondria in H-MSCs and E-MSCs. (C) Oxygraphy parameters were normalized by citrate synthase activity. (D) Mean fluorescence intensity detected by MitoSOX-based flow cytometry in H-MSCs and E-MSCs. Quantitative analysis of several antioxidant (E) and mitochondrial dynamics-related (F) genes in H-MSCs and E-MSCs by real-time RT-PCR. (G) Transmission electron microscopy to assess morphological features of mitochondria in H-MSCs and E-MSCs. Note mitochondrial elongation in E-MSCs (arrows). CAT, catalase; SOD2, superoxide dismutase 2; Nrf2, nuclear factor erythroid 2-related factor; GSH, glutathione; MFN1, mitofusin-1; MFN2, mitofusion-2; DNM1, dynamin-1. Data are expressed as means ± standard deviation of 5–6 samples in each group. *P < 0.05 vs. the H-MSC group.
FIGURE 4
FIGURE 4
Representative immunoblotting showing mitofusin-1 (MFN1), mitofusin-2 (MNF2), dynamin-related protein 1 (DRP1), and β-actin in MSCs from health (H) and emphysematous (E) donors. Data are expressed (right panel) as the ratio between protein expression and β-actin obtained by densitometry of 2 samples in each group.
FIGURE 5
FIGURE 5
Mitochondrial transfer from healthy or emphysematous MSCs and EVs to alveolar macrophages (MΦ). (A) Intensity of MitoRed fluorescence of healthy (H) or emphysematous (E) MSCs decreased after direct co-culture with MΦ (light blue and pink histograms, respectively). The extent of mitochondrial transfer to MΦ was measured by flow cytometry. Co-culture of MΦ with MitoRed-pretreated H-MSCs and E-MSCs resulted in increased MitoRed (APC+) mean fluorescent intensity of MΦ. (B) Scatter plots show MΦ and EV after 24 h in co-culture. The presence of CD45+ MΦ, demonstrating acquisition of MitoRed fluorescence (APC+), indicates that mitochondrial transfer occurs from H-EVs and E-EVs. Data are representative of three independent experiments. The histograms represented graphically in (A) are from a single representative experiment. *P < 0.05 vs. the MΦ + H-MSC.
FIGURE 6
FIGURE 6
Direct co-culture of MSCs and EVs from healthy or emphysematous donors modulates the alveolar macrophage (MΦ) profile. H-MSCs, 1 × 106 bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from healthy donors; E-MSCs, 1 × 106 BM-MSCs obtained from emphysematous donors; H-EVs, extracellular vesicles derived from 1 × 106 BM-MSCs obtained from healthy donors; E-EVs, extracellular vesicles derived from 1 × 106 BM-MSCs obtained from emphysematous donors. Data are expressed as medians (interquartile range) of 5–6 samples in each group. *P < 0.05 vs. MΦ. **P < 0.05 vs. the H-MSC. ***P < 0.05 vs. the E-MSC. &P < 0.05 vs. the H-EV.
FIGURE 7
FIGURE 7
Levels of IL-1β (A), IL-10 (B), and TGF-β (C) in lung tissue. C, intratracheal instillation of 50 μL of saline; ELA, intratracheal instillation of 0.2 IU of pancreatic porcine elastase; SAL, intravenous injection of 50 μL of saline; H-MSCs, 1 × 106 bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from healthy donors; E-MSCs, 1 × 106 BM-MSCs obtained from emphysematous donors; H-EVs, extracellular vesicles derived from 1 × 106 BM-MSCs obtained from healthy donors; E-EVs, extracellular vesicles derived from 1 × 106 BM-MSCs obtained from emphysematous donors. IL-1β, interleukin-1β; IL-10, interleukin-10; TGF-β, transforming growth factor-β. Data are expressed as means ± standard deviation of 7–10 animals/group. *P < 0.05 vs. the C group. #P < 0.05 vs. the ELA-SAL group. **P < 0.05 vs. the H-MSC group.
FIGURE 8
FIGURE 8
Echocardiographic analysis. Parasternal short axis view of both ventricles (upper panel) and pulmonary artery flow dynamics (lower panel). (A) Pulmonary artery acceleration time/pulmonary artery ejection time ratio (PAT/PET) and (B) right ventricle area. C, intratracheal instillation of 50 μL of saline; ELA, intratracheal instillation of 0.2 IU of pancreatic porcine elastase; SAL, intravenous injection of 50 μL of saline; H-MSCs, 1 × 106 bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from healthy donors; E-MSCs, 1 × 106 BM-MSCs obtained from emphysematous donors; H-EVs: extracellular vesicles derived from 1 × 106 BM-MSCs obtained from healthy donors; E-EVs, extracellular vesicles derived from 1 × 106 BM-MSCs obtained from emphysematous donors. RV, right ventricle. Data are expressed as means ± standard deviation of 7–10 animals/group. *P < 0.05 vs. the C group. #P < 0.05 vs. the ELA-SAL group.
FIGURE 9
FIGURE 9
Effects of H-MSCs, E-MSCs, H-EVs or E-EVs treatments on the remodeling process. Left panels: representative photomicrographs of lung parenchyma stained with Masson’s trichome staining collagen fibers in airways, (A); walls of blood vessels in interlobular septa, (B) and Weigert’s resorcin fuchsin elastic fibers in alveolar septa, (C). Note that blood vessels are highlighted by red arrowheads, elastic fibers by black arrowheads, and hyperinflated areas by red asterisks. C: intratracheal instillation of 50 μL of saline; ELA: intratracheal instillation of 0.2 UI of pancreatic porcine elastase (PPE); SAL: intravenous injection of 50 μL of saline; H-MSCs: 1 × 106 bone marrow mesenchymal stromal cells obtained from healthy donor; E-MSCs: 1 × 106 bone marrow mesenchymal stromal cells obtained from emphysematous donor; H-EVs: extracellular vesicles derived from 1 × 106 bone marrow mesenchymal stromal cells obtained from healthy donor; E-EVs: extracellular vesicles derived from 1 × 106 bone marrow mesenchymal stromal cells obtained from emphysematous donor. Right panels: Data are expressed as mean + SD of 5–7 animals/group. *vs. C group (p < 0.05). #Vs. ELA-SAL group (p < 0.05).

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