Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppress Hyperoxia-Induced Transdifferentiation of Rat Alveolar Type 2 Epithelial Cells

Bronchopulmonary dysplasia (BPD) remains the most important respiratory morbidity of preterm infants with few effective preventive strategies. Administration of mesenchymal stem cells (MSC) was considered effective to prevent BPD via paracrine extracellular vesicles (EVs), while appropriate regimens of MSC-EVs and the mechanism remain unclear. Therefore, we established a hyperoxia-induced rat BPD model, and examined the effect of early intraperitoneal MSC-EVs with different doses on BPD. We found that MSC-EVs ameliorated hyperoxia-induced lung injury in a dose-dependent manner, and high-dose MSC-EVs ameliorated alveolar simplification and fibrosis. Also, MSC-EVs showed its beneficial effects on vascular growth and pulmonary hypertension. Primary AT2 cells were observed to transdifferentiate into AT1 cells when exposure to hyperoxia in vitro. Administration of MSC-EVs at the first-day culture significantly delayed the transdifferentiation of AT2 cells induced by hyperoxia. We further found that exposure to hyperoxia led to elevated expression of WNT5a mRNA and protein, a key agent in AT2 transdifferentiation, while MSC-EVs administration decreased it. Further study is warranted that MSC-EVs may delay the transdifferentiation of AT2 cells via WNT5a. These studies provide key preclinical evidence of MSC-EVs therapeutics on BPD and highlight the effect of MSC-EVs on suppressing the transdifferentiation of AT2 cells and its possible mechanism through downregulation of WNT5a.