Prenatal FGFR2 Signaling via PI3K/AKT Specifies the PDGFRA⁺ Myofibroblast

Area of Science:

• Developmental Biology
• Cell Biology
• Pulmonary Medicine

Background:

• Fibroblast growth factor receptor 2 (FGFR2) signaling is crucial for lung development, regulating alveolar type 1 (AT1) and AT2 cell differentiation during the saccular phase.
• Platelet-derived growth factor receptor-α (PDGFRA)-positive lung fibroblasts comprise three subtypes: myofibroblasts, matrix fibroblasts, and lipofibroblasts, all essential for alveolarization.
• FGFR2 signaling is known to influence myofibroblast differentiation post-pneumonectomy, but its role during the saccular phase remains unclear.

Purpose of the Study:

• To investigate the role of FGFR2 signaling in regulating PDGFRA+ fibroblast differentiation during lung sacculation.
• To determine the impact of FGFR2 signaling inhibition on fibroblast and epithelial cell differentiation during lung development.

Main Methods:

• Temporal inhibition of FGFR2 signaling using a secreted dominant-negative FGFR2b (dnFGFR2) expressed by AT2 cells from embryonic day 16.5 to 18.5.
• Analysis of fibroblast and epithelial cell differentiation at embryonic day 18.5 and postnatal days 7 and 21.
• Assessment of fibroblast function using organoid models and in vitro treatment with recombinant dnFGFR2b/c and PI3K/AKT activator (740 Y-P).

Main Results:

• Inhibition of FGFR2 signaling led to a reduction in myofibroblasts and an increase in lipo-/matrix fibroblasts at all analyzed time points.
• Postnatal analysis revealed an increase in AT2 cells and a decrease in AT1 cells in lungs with inhibited FGFR2 signaling.
• In vitro studies showed reduced myofibroblast contraction upon dnFGFR2b/c treatment, which was rescued by PI3K/AKT activation.

Conclusions:

• FGFR2 signaling in AT2 cells during lung sacculation is essential for proper myofibroblast differentiation and maintenance of the fibroblast niche.
• Disruption of FGFR2 signaling alters fibroblast subtype balance, leading to impaired AT1 and AT2 cell differentiation and potentially affecting lung structure.
• The PI3K/AKT pathway plays a role in mediating FGFR2 signaling's effects on myofibroblast differentiation during lung development.