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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
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Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

Matthew R Riccetti1,2, Mereena George Ushakumary1, Marion Waltamath1

  • 1The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, and.

JCI Insight
|February 3, 2022
PubMed

Insights

Bronchopulmonary dysplasia (BPD) in premature infants involves fibroblast changes. Hyperoxia impairs PDGFRA+ fibroblasts, affecting lung development, but WNT activation may restore function.

Area of Science:

  • Pulmonary Medicine
  • Developmental Biology
  • Cell Biology

Background:

  • Bronchopulmonary dysplasia (BPD) affects up to 50% of premature infants, characterized by impaired lung alveolarization and microvascular development.
  • PDGFRA+ fibroblasts are crucial for lung development, and their reduction is implicated in BPD pathogenesis.
  • Understanding fibroblast heterogeneity and activation is key for developing targeted BPD therapies.

Purpose of the Study:

  • To investigate the heterogeneity and functional changes of PDGFRA+ fibroblasts during neonatal hyperoxia-induced lung injury and repair.
  • To identify therapeutic targets for BPD by analyzing fibroblast responses to hyperoxia.

Main Methods:

  • Utilized a neonatal hyperoxia mouse model (90% O2, P0-P7).
  • Sorted and analyzed PDGFRA+ fibroblasts during injury and recovery phases.
  • Performed in vitro contractility assays and generated lung organoids.

Main Results:

  • Hyperoxia decreased PDGFRA+ matrix/myofibroblasts and increased lipofibroblasts; these populations recovered by P10.
  • Hyperoxia-exposed PDGFRA+ fibroblasts showed reduced contractility and impaired alveolar type 1 cell differentiation in organoids.
  • Pathway analysis revealed reduced WNT signaling in hyperoxia fibroblasts.
  • WNT activation in organoids partially restored alveolar development and enhanced type 2 cell differentiation.

Conclusions:

  • Neonatal hyperoxia alters PDGFRA+ fibroblast populations and function, impairing lung development.
  • Reduced WNT signaling in fibroblasts contributes to BPD-like lung changes.
  • Targeting WNT signaling may offer a therapeutic strategy for BPD.

Keywords:
DevelopmentFibrosisGrowth factorsMouse modelsPulmonology

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