Gene Expression Signatures Point to a Male Sex-Specific Lung Mesenchymal Cell PDGF Receptor Signaling Defect in Infants Developing Bronchopulmonary Dysplasia

Abstract

Male sex is a risk factor for development of bronchopulmonary dysplasia (BPD), a common chronic lung disease following preterm birth. We previously found that tracheal aspirate mesenchymal stromal cells (MSCs) from premature infants developing BPD show reduced expression of PDGFRα, which is required for normal lung development. We hypothesized that MSCs from male infants developing BPD exhibit a pathologic gene expression profile deficient in PDGFR and its downstream effectors, thereby favoring delayed lung development. In a discovery cohort of 6 male and 7 female premature infants, we analyzed the tracheal aspirate MSCs transcriptome. A unique gene signature distinguished MSCs from male infants developing BPD from all other MSCs. Genes involved in lung development, PDGF signaling and extracellular matrix remodeling were differentially expressed. We sought to confirm these findings in a second cohort of 13 male and 12 female premature infants. mRNA expression of PDGFRA, FGF7, WNT2, SPRY1, MMP3 and FOXF2 were significantly lower in MSCs from male infants developing BPD. In female infants developing BPD, tracheal aspirate levels of proinflammatory CCL2 and profibrotic Galectin-1 were higher compared to male infants developing BPD and female not developing BPD. Our findings support a notion for sex-specific differences in the mechanisms of BPD development.

CCR2 Mediates Chronic LPS-Induced Pulmonary Inflammation and Hypoalveolarization in a Murine Model of Bronchopulmonary Dysplasia

“…MSC lines from six premature infants were incubated with TNF- α for 48 h. TNF- α decreased the mRNA and protein expression of PDGFRA ( Figures 8A, B ). Also decreased was the mRNA expression of WNT2, FOXF2, and SPRY1 genes ( Figure 8A ) required for normal mesenchymal cell function and lung development ( 66 ). TNF- α increased the mRNA expression of CCL2 and IL-6 ( Figure 6A ), creating a possible feed forward mechanism to promote inflammation and recruitment of inflammatory cells.…”

FOXF2 acts as a crucial molecule in tumours and embryonic development

“…The FOXF2 protein is commonly found in animals 6 . Many studies have demonstrated that FOXF2 has vital effects on the embryonic development of the lip, tooth, tongue, eye, cochlea, palate, cerebrum, gastrointestinal (GI) tract, bronchus, lung, tendon, diaphragm, cartilage and heart 3,4,[45][46][47][48][49][50][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89] . The following is an overview of the association between FOXF2 and diseases mainly related to malformations that occur in these different tissue locations.…”

“…Meanwhile, the study also shows a connection between the low expression of FOXF2 and bronchopulmonary dysplasia in infants 85 . Foxf2 in mice could be detected in the developing lung mesenchyme, while Foxp2, another pivotal molecule functioning in regulating lung gene expression, is found in the bronchial epithelium, indicating that Foxf2 plays a specific role in the development of the embryonic lung 86 .…”

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

“…Saa3 has been shown to be upregulated in a lamb preterm lung injury model 18 and to regulate Pdgfra 19 , which has a well established role in lung development in animal models [20][21][22] . Decreased PDGFRA expression was associated with increased risk for male patients to develop BPD 23 . The expression of Pdgfra was strongly decreased by hyperoxia in Fibroblasts 2 and Matrix fibroblasts at P14 ( Fig.…”