title: A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology.
abstract: Bronchopulmonary dysplasia (BPD) is a leading complication of premature birth and occurs primarily in infants delivered during the saccular stage of lung development. Histopathology shows decreased alveolarization and a pattern of fibroblast proliferation and differentiation to the myofibroblast phenotype. Little is known about the molecular pathways and cellular mechanisms that define BPD pathophysiology and progression. We have developed a novel three-dimensional human model of the fibroblast activation associated with BPD, and using this model we have identified the Notch pathway as a key driver of fibroblast activation and proliferation in response to changes in oxygen. Fetal lung fibroblasts were cultured on sodium alginate beads to generate lung organoids. After exposure to alternating hypoxia and hyperoxia, the organoids developed a phenotypic response characterized by increased α-smooth muscle actin (α-SMA) expression and other genes known to be upregulated in BPD and also demonstrated increased expression of downstream effectors of the Notch pathway. Inhibition of Notch with a γ-secretase inhibitor prevented the development of the pattern of cellular proliferation and α-SMA expression in our model. Analysis of human autopsy tissue from the lungs of infants who expired with BPD demonstrated evidence of Notch activation within fibrotic areas of the alveolar septae, suggesting that Notch may be a key driver of BPD pathophysiology.
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California;
authors.forename: Jennifer M S
authors.initials: JM
authors.lastname: Sucre
authors.affiliation: UCLA Department of Materials Science and Engineering, UCLA, Los Angeles, California;
authors.forename: Dan
authors.initials: D
authors.lastname: Wilkinson
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California; and.
authors.forename: Preethi
authors.initials: P
authors.lastname: Vijayaraj
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California;
authors.forename: Manash
authors.initials: M
authors.lastname: Paul
authors.affiliation: UCLA Department of Materials Science and Engineering, UCLA, Los Angeles, California;
authors.forename: Bruce
authors.initials: B
authors.lastname: Dunn
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California;
authors.forename: Jackelyn A
authors.initials: JA
authors.lastname: Alva-Ornelas
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California; Pulmonary Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California; and Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, California bgomperts@mednet.ucla.edu.
authors.forename: Brigitte N
authors.initials: BN
authors.lastname: Gomperts
mesh_terms: D000464:Alginates / Q000737:chemistry; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000464:Alginates; D003470:Culture Media; D006603:Hexuronic Acids; D051880:Receptors, Notch; D020723:Glucuronic Acid
keywords: development; disease modeling; fibrosis; lung prematurity; signaling pathways