Vascular endothelial growth factor mediates the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicles against neonatal hyperoxic lung injury

We previously reported the role of vascular endothelial growth factor (VEGF) secreted by mesenchymal stem cells (MSCs) in protecting against neonatal hyperoxic lung injuries. Recently, the paracrine protective effect of MSCs was reported to be primarily mediated by extracellular vesicle (EV) secretion. However, the therapeutic efficacy of MSC-derived EVs and the role of the VEGF contained within EVs in neonatal hyperoxic lung injury have not been elucidated. The aim of the study was to determine whether MSC-derived EVs attenuate neonatal hyperoxic lung injury and, if so, whether this protection is mediated via the transfer of VEGF. We compared the therapeutic efficacy of MSCs, MSC-derived EVs with or without VEGF knockdown, and fibroblast-derived EVs in vitro with a rat lung epithelial cell line challenged with H 2 O 2 and in vivo with newborn Sprague-Dawley rats exposed to hyperoxia (90%) for 14 days. MSCs (1 × 10 5 cells) or EVs (20 µg) were administered intratracheally on postnatal day 5. The MSCs and MSC-derived EVs, but not the EVs derived from VEGF-knockdown MSCs or fibroblasts, attenuated the in vitro H 2 O 2 -induced L2 cell death and the in vivo hyperoxic lung injuries, such as impaired alveolarization and angiogenesis, increased cell death, and activated macrophages and proinflammatory cytokines. PKH67-stained EVs were internalized into vascular pericytes (22.7%), macrophages (21.3%), type 2 epithelial cells (19.5%), and fibroblasts (4.4%) but not into vascular endothelial cells. MSC-derived EVs are as effective as parental MSCs for attenuating neonatal hyperoxic lung injuries, and this protection was mediated primarily by the transfer of VEGF. Neonatal lung damage: Vesicles as vehicles for treatment Membrane-bound sacs called vesicles, secreted by stem cells, carry a protein that might prevent oxygen damaging the lungs of newborn infants. This damage is particularly prevalent in babies born prematurely. The ‘mesenchymal’ stem cells generate cells of connective tissue, blood and blood vessels. They produce vascular endothelial growth factor (VEGF), a protein known to allow the stem cells to protect against neonatal lung injuries caused by oxygen. In studies with rats, Jee-Yin Ahn, Yun Sil Chang and colleagues at Sungkyunkwan University in South Korea, found secreted vesicles carrying VEGF are as effective as the whole stem cells. They also confirmed that the effect was specifically due to the VEGF. The research extends understanding of the protec