Impaired angiogenic supportive capacity and altered gene expression profile of CD146+ mesenchymal stromal cells isolated from hyperoxia-injured neonatal rat lungs

Background: Bronchopulmonary dysplasia (BPD), a common adverse outcome of extreme preterm birth, can be caused by oxygen-related lung injury and is characterized by arrested alveolar development. Mesenchymal stromal cells (MSCs) have lung protective effects. Conversely, BPD is associated with increased MSCs in tracheal aspirates. This apparent discrepancy is unexplored. We hypothesized that endogenous lung (L-)MSCs are perturbed in an oxygen-induced rat model mimicking BPD. Methods: Rat pups were exposed to 21% or 95% O2 from postnatal day 0 to 10. On day 12, CD146+ L-MSCs were isolated and characterized. Epithelial and vascular repair potential were tested by scratch assay and endothelial network formation respectively, immune function by mixed lymphocyte reaction assay. Microarray analysis was performed using GSEA software. Results: L-MSCs isolated from hyperoxia rat pups had decreased CD73 expression and inhibited lung endothelial network formation. L-MSCs indiscriminately promoted epithelial wound healing and limited T-cell proliferation. Expression of anti-angiogenic genes of the axonal guidance cue pathway was increased after in vivo hyperoxia, whereas genes of the anti-inflammatory JAK/STAT and lung/vascular growth promoting FGF pathways were decreased. Conclusions: In vivo hyperoxia exposure alters the pro-angiogenic effects and FGF expression of L-MSCs. Additionally, decreased CD73 and JAK/STAT expression suggest decreased immune function. L-MSC function may be perturbed and contribute to BPD pathogenesis. These findings may lead to improvements in manufacturing exogenous MSCs with superior repair capabilities.