Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs.

Abstract

Novel therapies are needed for bronchopulmonary dysplasia (BPD) because no effective treatment exists. Mesenchymal stromal cell extracellular vesicles (MSC-sEVs) have therapeutic efficacy in a mouse pup neonatal hyperoxia BPD model. We tested the hypothesis that MSC-sEVs will improve lung functional and structural development in mechanically ventilated preterm lambs. Preterm lambs (~129d; equivalent to human lung development at ~28w gestation) were exposed to antenatal steroids, surfactant, caffeine citrate, and supported by mechanical ventilation for 6-7d. Lambs were randomized to blinded treatment with either MSC-sEVs (human bone marrow MSC-derived; 2x1011 particles iv; n=8; 4F/4M) or vehicle control (saline iv; 4F/4M). Treatment was at 6 and 78 hours post-delivery. Physiological targets were pulse oximetry O2 saturation 90-94% (PaO2 60-90 mmHg), PaCO2 45-60 mmHg (pH 7.25-7.35), and tidal volume 5-7 mL/Kg. MSC-sEVs-treated preterm lambs tolerated enteral feedings and maintained weight compared to the vehicle control group. Respiratory severity score, oxygenation index, A-a gradient, distal airspace wall thickness, and smooth muscle thickness around terminal bronchioles and pulmonary arterioles were lower (*) for the MSC-sEVs group versus the vehicle controls. S/F ratio, radial alveolar count, secondary septal volume density, alveolar capillary surface density, and protein abundance of VEGF-R2 were higher (*) for the MSC-sEVs versus the vehicle control group. MSC-sEVs improved respiratory system physiology and alveolar formation in mechanically ventilated preterm lambs. MSC-sEVs may be an effective and safe therapy for appropriate functional and structural development of the lung in preterm infants who require mechanical ventilation and are at-risk of developing BPD.