Impaired Angiogenic Supportive Capacity and Altered Gene Expression Profile of Resident CD146⁺Mesenchymal Stromal Cells Isolated from Hyperoxia-Injured Neonatal Rat Lungs

Abstract

Bronchopulmonary dysplasia (BPD), the most common complication of extreme preterm birth, can be caused by oxygen-related lung injury and is characterized by impaired alveolar and vascular development. Mesenchymal stromal cells (MSCs) have lung protective effects. Conversely, BPD is associated with increased MSCs in tracheal aspirates. We hypothesized that endogenous lung (L-)MSCs are perturbed in a well-established oxygen-induced rat model mimicking BPD features. Rat pups were exposed to 21% or 95% oxygen from birth to postnatal day 10. On day 12, CD146 L-MSCs were isolated and characterized according to the International Society for Cellular Therapy criteria. 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 the Affymetrix GeneChip and gene set enrichment analysis software. CD146 L-MSCs isolated from rat pups exposed to hyperoxia had decreased CD73 expression and inhibited lung endothelial network formation. CD146 L-MSCs indiscriminately promoted epithelial wound healing and limited T cell proliferation. Expression of potent antiangiogenic genes of the axonal guidance cue and CDC42 pathways was increased after in vivo hyperoxia, whereas genes of the anti-inflammatory Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and lung/vascular growth-promoting fibroblast growth factor (FGF) pathways were decreased. In conclusion, in vivo hyperoxia exposure alters the proangiogenic effects and FGF expression of L-MSCs. In addition, decreased CD73 and JAK/STAT expression suggests 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.

CPEB2-activated PDGFRα mRNA translation contributes to myofibroblast proliferation and pulmonary alveologenesis

“…Consequently, CPEB2-KO mice surviving to adulthood show pulmonary dysfunction with decreased elastance and resistance, similar to other emphysema-like mouse models and human BPD [28][29][30]. Moreover, we analyzed 2 GEO datasets and found decreased CPEB2 mRNA level in umbilical cords of BPD infants [31] and hyperoxiaexposed pulmonary MSCs [32]. In summary, CPEB2 plays an important role in alveologenesis and may be a potential therapeutic target for BPD.…”

“…GSE8586 study involved using Affymetrix Human Genome U133 Plus 2.0 array to profile transcriptomes of umbilical cord tissues isolated from premature newborns in whom BPD developed or not [31]. The other GSE99633 study involved isolated CD146 + lung MSCs from P12 rat pups exposed to 95% or 21% O 2 from birth to P10 [32]. The mRNA levels of designated targets were extracted.…”

“…7a, P < 0.05). In the other study (GSE99633), newborn rats under 95% hyperoxia for 10 days were sacrificed at P12 to isolate lung CD146 + MSCs [32]. Because these CD146 + MSCs also contain a PDGFRα-expressing MYF lineage during the alveolar stage of lung development [4], we analyzed this dataset and found a significant reduction in CPEB2 and PDGFRα mRNA levels in hyperoxia-exposed pulmonary MSCs ( Fig.…”

Oxygen and mechanical ventilation impede the functional properties of resident lung mesenchymal stromal cells

“…MSCs were isolated from whole lung tissue as per a previously described methodology [9]. Briefly, residual large airways were removed and discarded.…”

“…Preterm neonates experience bouts of hyperoxia, inflammation, and ventilator-induced lung injury. Recent animal studies by Collins et al demonstrated that the repair potential of L-MSCs isolated from a rat model of hyperoxia-induced BPD was altered [9]. Furthermore, studies by Popova and colleagues suggest that the presence of MSCs in tracheal aspirates of preterm newborns was a predictor for developing BPD [10].…”