ANTI-INFLAMMATORY SMALL EXTRACELLULAR VESICLES FROM MESENCHYMAL STROMAL CELLS IMPROVE DONOR LUNG PRESERVATION

NATALIA PACIENZA ; CECILIA SANMARTIN ; MARTIN MARCOS ; DIEGO SANTA-CRUZ; OSCAR ROBLEDO ; GUSTAVO YANNARELLI; RICARDO MALVICINI; ALEJANDRO BERTOLOTTI

Congreso; LXV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2020

Infusion of human mesenchymal stromal cells (MSCs) during donor lung ablation improves organ preservation by reducing oxidative damage and inflammation. Here, we studied whether the secretion of small extracellular vesicles (sEVs) mediates these beneficial effects. The rat lung preservation model used here consisted of: cardiac arrest, warm ischemia (2h), cold ischemia (1.5h), and normothermic ex-vivo lung perfusion (EVLP, 1h). Human umbilical cord-derivedMSCs (1x10^6 cells) or their secreted sEVs were administered via the pulmonary artery after 1h of warm ischemia. A decrease in lung compliance indicates poor graft quality, and it was determined from pressure-volume curves at baseline and after warm ischemia or EVLP. Small-EVs were purified from MSC-conditioned medium by anion-exchange chromatography. They were positive for CD63- and CD81-antigen, and showed the typical size (mean 137 nm, range 90-190 nm) and morphology by nanoparticle tracking analysis and electron microscopy, respectively. Moreover, sEVs significantly suppressed the M1 phenotype acquisition in LPS-stimulated RAW264.7 macrophages (53% respect to control). Interestingly, sEVs inhibited tissue damage quickly. After warm ischemia, lung compliance dropped by 42% in the sEVs-treated group, while vehicle and MSCs groups showed a stronger reduction (73% and 76%, respectively). Warm ischemia also produced edema in all groups. Noteworthy, the benefit of EVLP on recovering edema and lung function was moreevident in treated groups. Lung compliance significantly dropped by 62% between baseline and EVLP in the vehicle group, whereas MSCs and sEVs protected lung function as evidenced by a smaller decrease (35% and 27%, respectively). These data indicate that MSC-derived sEVs play a key role in preserving lung function. Compared to cell therapy, sEVs provide rapid protection of the organ and have a superior safety profile. Thus, sEVs may represent an innovative cell-free therapy for organ preservation.