Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis.

Area of Science:

• Developmental Biology
• Molecular Biology
• Pulmonology

Background:

• The Hedgehog (HH) signaling pathway is vital for embryonic development, including lung formation in mice.
• Its role in human lung development and its potential involvement in pulmonary hypoplasia remain less understood.

Purpose of the Study:

• To investigate the necessity of the HH pathway for human lung branching.
• To determine if HH pathway dysfunction contributes to pulmonary hypoplasia, specifically in congenital diaphragmatic hernia (CDH).

Main Methods:

• Analysis of single-cell and bulk RNA-sequencing data from human fetal lungs.
• In vitro culture of human fetal lung segments with an SHH inhibitor (5E1).
• Assessment of gene and protein markers for lung development and signaling pathways.

Main Results:

• HH pathway components show early, regulated expression during human lung development.
• Inhibition of HH signaling reduced lung branching and dysregulated epithelial (SOX2, SOX9) and mesenchymal (ACTA2) progenitor markers.
• FGF and Wnt signaling pathways were disrupted; HH elements were downregulated in CDH lung tissues.

Conclusions:

• HH signaling is essential for proper human lung branching and development.
• HH pathway inhibition negatively impacts lung development, affecting key progenitor markers and cross-talk with FGF and Wnt pathways.
• Downregulation of HH signaling in CDH suggests a role in this congenital lung disease, highlighting potential therapeutic targets.