The Genetic Architecture of Alveolar Formation in the Lung in the Context of Bronchopulmonary Dysplasia

Abstract

Alveologenesis is the most important and the least understood phase of lung development. Alveolar defects underlie both neonatal and adult lung diseases. Their arrested development is found in infants with BPD (BronchoPulmonary Dysplasia), while their destruction is characteristic of emphysematous lungs in adult COPD. We have developed 3 parallel, postnatal genetically‐based models to analyze the molecular basis of alveologenesis. Conditional postnatal inactivation of genes encoding receptors for TGFb, or PDGFA or IGF1 in a unique cell type we have identified as Secondary Crest Myofibroblasts, or SCMF blocks alveologenesis & produces a phenotype similar to human BPD. We reasoned that due to nearly identical phenotypes, the three BPD phenocopy models must share genetic elements whose role in alveologenesis is indispensable. To test this hypothesis, we have isolated mutant and control SCMF and identified their transcriptomic profile by RNA sequencing (RNAseq). Bioinformatic analysis of the sequencing data identified “pathway‐specific” differentially expressed genes (DEG) for TGFb, PDGFA/PDGFRa and IGF1 mutant models. Most importantly however, as predicted, we identified a cluster of “shared” genes which we propose contains conserved core alveologenesis regulatory genes. The accumulated evidence reveals a constellation of genes that makeup the genetic architecture of alveologenesis in mice with relevance to pathogenesis of BPD in human preterm neonates.Support or Funding InformationNIH/NHLBI & the Hastings Foundation