Bronchopulmonary Dysplasia with Pulmonary Hypertension Associates with Loss of Semaphorin Signaling and Functional Decrease in FOXF1 Expression

ABSTRACT: Lung injury in preterm infants leads to lifelong structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD). In its most severe form BPD is accompanied by pulmonary hypertension (PH). While impaired alveologenesis and vasculogenesis in BPD are well-described, the molecular mechanisms driving these phenotypes and the cellular dynamics associated with evolving BPD and BPD+PH in humans are not well-described. We performed single-cell RNA sequencing on preterm infant lungs in early stages of BPD, BPD+PH and term infants. Analysis of the endothelium revealed an aberrant capillary cell-state primarily in BPD+PH marked by ANKRD1 expression and a transcriptomic signature not previously described in previously analyzed human lung disease, a finding validated in an expanded repository of human infant lung tissue. Predictive signaling analysis identified deficits in the semaphorin guidance-cue signaling pathway and decreased expression of pro-angiogenic transcription factor FOXF1 within the alveolar parenchyma of the human neonatal lung samples with BPD and BPD+PH. We observed similar trends in the in decreased semaphoring signaling in a murine BPD mouse model and in analysis of ACDMPV single-nuclear sequencing data. These transcriptional deficits in semaphorin signaling common to BPD+PH and ACDMPV suggest a mechanistic link between the developmental phenotype in BPD and ACDMPV, providing a foundation for further exploration of the role of semaphorins in normal alveolar development. Further, these data fill a critical gap in currently available transcriptomic analysis of the normal and diseased lung across the lifespan as searchable atlas of early human lung development and injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275938 | GEO | 2025/04/14

REPOSITORIES: GEO