C71-30 Pdgfrα⁺Acta2⁺Double-positive Fibroblasts Orchestrate Ipf Pathogenesis, and Targeted Ablation Yields Robust Therapeutic Benefit

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive extracellular matrix remodeling, irreversible distortion of alveolar architecture, and relentless decline in pulmonary function. Although antifibrotic therapies can modestly slow functional deterioration, they remain insufficient to effectively halt or reverse disease progression. Defining the specific mesenchymal populations that initiate and maintain fibrotic lesions is therefore essential for developing targeted interventions.

Methods

To identify the cellular drivers of fibrotic lesion formation, we focused on a Pdgfrα⁺Acta2⁺ double-positive fibroblast population and interrogated its fate and function in vivo. We employed a dual recombinase-based lineage tracing strategy to label this subset with high specificity, coupled with a conditional ablation system to selectively eliminate the same cells. Using a chronic lung fibrosis model, we performed multi-time-point analyses spanning the initiation, expansion, and maintenance phases of fibrosis. Spatiotemporal dynamics were quantified by histological mapping, fibrosis burden and collagen deposition assessments, and longitudinal evaluations of lung function.

Results

Across the full course of chronic fibrogenesis, Pdgfrα⁺Acta2⁺ double-positive fibroblasts emerged as the dominant fibroblast population associated with the onset and progression of fibrotic remodeling. Lineage tracing revealed a pronounced expansion and progressive accumulation of this subset within nascent and established lesions, with clear enrichment in regions of active matrix deposition and structural distortion. Notably, the magnitude of Pdgfrα⁺Acta2⁺ fibroblast expansion closely tracked lesion development, increased collagen deposition, and worsening lung functional parameters over time, supporting a tight coupling between cellular accumulation and disease severity. Importantly, targeted elimination of Pdgfrα⁺Acta2⁺ double-positive fibroblasts resulted in a marked reduction of fibrotic burden, attenuation of architectural destruction, and substantial improvement in functional impairment. Ablation significantly slowed the trajectory of disease progression across multiple stages, indicating a nonredundant requirement for this subset in sustaining chronic fibrosis.

Conclusions

These findings establish Pdgfrα⁺Acta2⁺ double-positive fibroblasts as a central cellular population that drives fibrotic lesion formation and maintenance in chronic pulmonary fibrosis. Selective depletion of this subset confers robust structural and functional benefits, highlighting Pdgfrα⁺Acta2⁺ fibroblasts as a promising therapeutic target for IPF.

This abstract is funded by: This study was supported by the National Key Research and Development Program of China grants 2016YFC1304000 (C Chen); The National Natural Scientific Foundation of China 82170017,82370085(C Chen); Zhejiang Provincial Key Research and Development Program 2020C03067 (C Chen)