Hedgehog and Platelet-derived Growth Factor Signaling Intersect during Postnatal Lung Development.

Area of Science:

• Pulmonary and Respiratory Medicine
• Developmental Biology
• Cell Signaling

Background:

• Normal lung development relies on Hedgehog (HH) and platelet-derived growth factor (PDGF) signaling for mesenchymal cell regulation.
• PDGF signaling is essential for postnatal alveolar septum formation by myofibroblasts.
• Previous work indicated HH signaling is also required for postnatal lung development and myofibroblast differentiation.

Purpose of the Study:

• To investigate the relationship between HH and PDGF signaling in murine postnatal lung development.
• To clarify how these pathways interact in regulating lung myofibroblasts during alveolar septation.

Main Methods:

• Utilized timed experiments and gene knockouts (Pdgfa, Pdgfra) to study lung myofibroblast phenotypes.
• Employed a dual signaling reporter (Gli1) to track HH and PDGF pathway activity.
• Performed bulk and single-cell RNA sequencing on lung cells to analyze gene expression changes.
• Investigated Gli-binding sites in PDGF target genes.

Main Results:

• HH inhibition mimicked the lung myofibroblast defects observed in Pdgfa and Pdgfra knockouts.
• HH and PDGF pathway intermediates were concurrently expressed during myofibroblast accumulation.
• HH inhibition decreased Pdgfra expression and reduced Pdgfra-positive cells.
• HH inhibition altered expression of both HH and PDGF target genes, suggesting HH input into PDGF signaling.

Conclusions:

• HH and PDGF signaling pathways converge to support myofibroblast/fibroblast function during secondary alveolar septum formation.
• This molecular interplay is crucial for normal lung alveolarization.
• Findings provide a basis for understanding perinatal lung diseases linked to impaired alveolar development.