Bronchopulmonary Dysplasia with Pulmonary Hypertension Associates with Loss of Semaphorin Signaling and Functional...

Area of Science:

• Neonatal respiratory medicine
• Molecular biology
• Developmental biology

Background:

• Infant lung injury can lead to bronchopulmonary dysplasia (BPD), a condition associated with structural and functional respiratory deficits.
• Severe BPD can progress to pulmonary hypertension (PH), impacting infant health outcomes.
• Understanding the cellular and molecular mechanisms driving BPD progression is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the cellular and molecular dynamics of evolving bronchopulmonary dysplasia (BPD) in preterm infants.
• To compare lung tissue from infants with early-stage BPD and BPD with pulmonary hypertension (PH) to that of term infants.
• To identify key molecular pathways and cell states involved in BPD pathogenesis.

Main Methods:

• Single-cell RNA sequencing was performed on lung tissue samples from preterm infants with BPD/BPD+PH and term infants.
• Endothelial cell states were analyzed to identify aberrant cell populations.
• Predictive signaling pathway analysis was used to identify molecular deficits.
• A murine BPD model and human samples with alveolar capillary dysplasia (ACDMPV) were used for validation.

Main Results:

• A unique aberrant capillary cell-state, characterized by *ANKRD1* expression, was identified in infants with BPD and PH.
• Deficits in the semaphorin guidance-cue signaling pathway were observed in the alveolar parenchyma of infants with BPD/BPD+PH.
• Decreased expression of the pro-angiogenic transcription factor *FOXF1* was found in BPD/BPD+PH lung samples.
• Loss of semaphorin signaling was replicated in a murine BPD model and in human ACDMPV cases.

Conclusions:

• Aberrant capillary cell states and semaphorin signaling pathway deficits are key features of BPD in preterm infants.
• Semaphorin signaling plays a critical role in normal lung development and may be mechanistically linked to BPD and ACDMPV.
• These findings provide insights into the developmental programs underlying BPD and ACDMPV, suggesting potential therapeutic targets.