O1041: Validation of Key Genetic Pathways in Compensatory Lung Growth via Meta-Analysis of Mouse Model Data in the Gene Expression Omnibus

Background: Compensatory lung growth (CLG) is defined as an absolute increase in the quantity of functional lung tissue after partial lung resection. CLG has been observed in mice, rats, cats, dogs, rabbits, and ferrets, occurring rapidly in the contralateral lung after pneumonectomy. This phenomenon is also observed in humans but appears largely relegated to infants and young children .

The mechanism for CLG remains incompletely understood. The molecular basis for CLG carried out over the past decade has broadened knowledge of the genetic pathways driving this phenomenon. However, results have not been replicated across all studies, possibly due to differences in design or sample size. We conducted a meta-analysis of gene expression in CLG across 6 different experiments within the Gene Expression Omnibus (GEO) and report upon those genes and pathways that are consistently up- and downregulated across studies.

Methods: GEO is an international public functional repository that archives and freely distributes genomics data submitted by the research community. Six studies containing control and experimental pneumonectomy data using mouse models were extracted from the GEO repository. Each study had a minimum of 2 samples in both the experimental and control groups. Meta-analysis was conducted using random effects model; vote counting; and a third process that used mean gene fold change and p-values from all six studies. Significantly up- and downregulated genes were evaluated using Gene Set Enrichment Analysis (GSEA). Network analysis (NA) was then used to identify genes with high topology.

Results: The observed transcriptomic patterns demonstrated regulation in mesenchymal cell signaling (FBN2, VEGF-C, IGFBP-3, ECM2, TGFBI), epithelial organogenesis (FAM83B, SPINT1, BARX2, CLDN23, WNT9B), and filament-based pathway (SHH, KRT16, PKP1, LNA, KRT14). The data also revealed early downregulation of pro-inflammatory cytokine transcripts although this gene set only met nominal significance thresholds. High topology genes and/or genes that met significance criteria for up- or downregulation were SPINT1 in the epithelial organogenesis pathway, SHH in the filament-based pathway, and ECM2 and VEGF-C in the mesenchymal transition pathway.

Conclusion: These data suggest that mesenchymal cell expression patterns, and specifically epithelial cell transition for organogenesis, in conjunction with genes within the filament-based pathway, are associated with the mechanism of CLG post-pneumonectomy. These findings validate the results of the individual studies that first reported them, but have not yet been replicated. Identification of SPINT1, SHH, ECM2, and VEGF-C as influential genes in CLG provides targets for future study.