TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice
Danielle A Callaway1,2, Ian J Penkala2,3, Su Zhou2,3,4
1Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Insights
Transforming growth factor beta 2 (TGF-β2) signaling is essential for maintaining alveolar epithelial cell type 1 (AT1) function and fate. Loss of TGF-β2 signaling in AT1 cells causes cell reprogramming and persistent lung architectural changes.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Cell Biology
Background:
- Premature birth impairs lung development, increasing bronchopulmonary dysplasia (BPD) risk.
- The TGF-β superfamily's role in BPD pathogenesis is known, but the affected cell lineage is unclear.
Purpose of the Study:
- To investigate the role of TGF-β receptor 2 (TGFbr2) in alveolar epithelial cell fate and function.
- To determine the impact of TGFbr2 loss in AT1 cells on lung development and architecture.
Main Methods:
- Utilized genetic models to delete TGFbr2 in AT1 cells during late lung development.
- Employed oligohydramnios model to restrict fetal lung stretch.
- Conducted transcriptomic and proteomic analyses.
Main Results:
- Loss of TGFbr2 in AT1 cells induced AT1-AT2 cell reprogramming and persistent pulmonary architectural alterations.
- Reduced fetal lung stretch exacerbated AT1-AT2 reprogramming.
- TGFbr2 is necessary for extracellular matrix production in AT1 cells, regulating integrin transcription and mechanotransduction.
Conclusions:
- TGF-β signaling is intrinsically required for maintaining AT1 cell fate and function.
- AT1 cells are key orchestrators of the alveolar matrisome, influenced by TGF-β signaling and mechanical forces.
Abstract:
Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
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