Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function

Area of Science:

• Pulmonary Medicine
• Developmental Biology
• Molecular Endocrinology

Background:

• Antenatal glucocorticoids improve preterm infant lung function.
• Mechanisms of glucocorticoid receptor (GR) signaling in fetal lung maturation are unclear.

Purpose of the Study:

• To elucidate cellular and molecular mechanisms of GR signaling in prenatal lung maturation.
• Identify specific cell types and pathways regulated by GR.

Main Methods:

• Utilized gene deletion models (mesenchymal, epithelial, endothelial) in mice.
• Integrated genome-wide gene expression, ATAC-seq, and single-cell RNA-seq.
• Analyzed GR deletion and activation effects on lung development.

Main Results:

• Mesenchymal-specific GR deletion impaired lung function, mimicking global deletion.
• GR promotes differentiation of mesenchymal progenitor cells into matrix fibroblasts.
• GR signaling regulates extracellular matrix genes and key signaling pathways (VEGF, JAK-STAT, WNT).
• Loss of mesenchymal GR signaling increased SOX9+ alveolar epithelial progenitor proliferation and inhibited AT2/AT1 cell differentiation.

Conclusions:

• GR signaling in mesenchymal cells is essential for fetal lung maturation.
• GR regulates fibroblast differentiation, impacting alveolar epithelial progenitor cell behavior.
• Identifies specific mesenchymal progenitor cells and pathways critical for glucocorticoid-mediated lung development.