title: Reduced platelet-derived growth factor receptor expression is a primary feature of human bronchopulmonary dysplasia.
abstract: Animal studies have shown that platelet-derived growth factor (PDGF) signaling is required for normal alveolarization. Changes in PDGF receptor (PDGFR) expression in infants with bronchopulmonary dysplasia (BPD), a disease of hypoalveolarization, have not been examined. We hypothesized that PDGFR expression is reduced in neonatal lung mesenchymal stromal cells (MSCs) from infants who develop BPD. MSCs from tracheal aspirates of premature infants requiring mechanical ventilation in the first week of life were studied. MSC migration was assessed in a Boyden chamber. Human lung tissue was obtained from the University of Rochester Neonatal Lung Biorepository. Neonatal mice were exposed to air or 75% oxygen for 14 days. PDGFR expression was quantified by qPCR, immunoblotting, and stereology. MSCs were isolated from 25 neonates (mean gestational age 27.7 wk); 13 developed BPD and 12 did not. MSCs from infants who develop BPD showed lower PDGFR-α and PDGFR-β mRNA and protein expression and decreased migration to PDGF isoforms. Lungs from infants dying with BPD show thickened alveolar walls and paucity of PDGFR-α-positive cells in the dysmorphic alveolar septa. Similarly, lungs from hyperoxia-exposed neonatal mice showed lower expression of PDGFR-α and PDGFR-β, with significant reductions in the volume of PDGFR-α-positive alveolar tips. In conclusion, MSCs from infants who develop BPD hold stable alterations in PDGFR gene expression that favor hypoalveolarization. These data demonstrate that defective PDGFR signaling is a primary feature of human BPD.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Antonia P
authors.initials: AP
authors.lastname: Popova
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Tracy X
authors.initials: TX
authors.lastname: Cui
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Richardson
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Linn
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Adam M
authors.initials: AM
authors.lastname: Goldsmith
authors.affiliation: Department of Pediatrics, University of Rochester, Rochester, New York.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Pryhuber
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and mhershen@umich.edu.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: PDGFR-α; PDGFR-β; hyperoxia; lung development; prematurity