Related Experiment Video
Updated: Jun 1, 2026
Refined Murine Model of Idiopathic Pulmonary Fibrosis
Published on: June 17, 2025
Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice
Stephen E McGowan1, Diann M McCoy
1Department of Veterans Affairs Research Service, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. stephen-mcgowan@uiowa.edu
Abstract:
In mice, secondary alveolar septal formation primarily occurs during a brief postnatal period and is accompanied by transient expansion of the interstitial lung fibroblast (LF) population. PDGF-A, which solely signals through PDGF-receptor-alpha (PDGF-Rα), is required for expansion, but the receptor's relevant downstream targets remain incompletely defined. We have evaluated the proliferation, apoptosis, and differential response to the selective protein tyrosine kinase inhibitor, imatinib, by pdgfrα-expressing LF (pdgfrα-LF) and compared them with their nonexpressing LF counterparts. Our objective was to determine whether diminished signaling through PDGF-Rα-mediated pathways regulates the decline in myofibroblasts, which accompanies septal thinning and ensures more efficient alveolar gas exchange. Using quantitative stereology and flow cytometry at postnatal d 12 and 14, we observed that imatinib caused a selective suppression of proliferation and an increase in apoptosis. The number of the alpha smooth muscle actin (αSMA) producing pdgfrα-LF was also reduced. Using cultures of neonatal mouse LF, we showed that imatinib did not suppress PDGF-Rα gene expression but reduced PDGF-A-mediated Akt phosphorylation, potentially explaining the increase in apoptosis. Our findings are relevant to bronchopulmonary dysplasia in which positive pressure ventilation interferes with myofibroblast depletion, septal thinning, and capillary maturation.
Insights
PDGF-A signaling through PDGF-receptor-alpha regulates lung fibroblast proliferation and apoptosis during postnatal development. Inhibiting this pathway impacts myofibroblast populations, crucial for alveolar gas exchange and relevant to lung injury models.
Area of Science:
- Pulmonary Biology
- Cell Biology
- Developmental Biology
Background:
- Secondary alveolar septal formation in mice is a postnatal process involving interstitial lung fibroblast (LF) expansion.
- Platelet-derived growth factor A (PDGF-A) signaling via PDGF-receptor-alpha (PDGF-Rα) is essential for this expansion, but downstream targets are unclear.
- Myofibroblast populations decline during septal thinning, optimizing alveolar gas exchange.
Purpose of the Study:
- To investigate the role of PDGF-Rα signaling in regulating lung fibroblast proliferation, apoptosis, and myofibroblast populations.
- To determine if inhibiting PDGF-Rα signaling affects the decline in myofibroblasts during lung development.
- To explore the therapeutic potential of targeting PDGF-Rα in lung injury contexts like bronchopulmonary dysplasia.
Main Methods:
- Quantitative stereology and flow cytometry were used to analyze lung fibroblasts at postnatal days 12 and 14 in mice.
- The selective protein tyrosine kinase inhibitor, imatinib, was employed to assess the effects on pdgfrα-expressing LF (pdgfrα-LF) and non-expressing LF.
- Primary neonatal mouse LF cultures were used to study gene expression and protein phosphorylation.
Main Results:
- Imatinib selectively suppressed proliferation and increased apoptosis in pdgfrα-LF.
- The number of alpha smooth muscle actin (αSMA)-positive pdgfrα-LF was significantly reduced by imatinib treatment.
- In cultured LF, imatinib reduced PDGF-A-mediated Akt phosphorylation without affecting PDGF-Rα gene expression, suggesting a mechanism for increased apoptosis.
Conclusions:
- PDGF-Rα signaling critically regulates lung fibroblast proliferation and survival during postnatal lung development.
- Targeting PDGF-Rα pathways may influence myofibroblast dynamics, impacting alveolar septal thinning and gas exchange.
- These findings have implications for understanding and potentially treating conditions like bronchopulmonary dysplasia, where abnormal myofibroblast persistence hinders lung maturation.
