An Unexpected Beneficial Role of PDGF Signaling in Pulmonary Fibrosis

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Abstract Rationale: PDGF regulates mesenchymal differentiation and proliferation in developing lung, and upon injury. Aberrant PDGF signaling is implicated in idiopathic pulmonary fibrosis (IPF). However, while in preclinical fibrosis models inhibition of PDGF signaling with Imatinib decreased lung fibrosis, the same treatment failed to halt progressive fibrosis in patients with established IPF. Work of others suggests that upregulated PDGFA signaling in fibroblasts supports alveolar regeneration in aged mice following pneumonectomy. Collectively, these observations question the ‘deleterious’ role of PDGF signaling during lung fibrosis and whether it exerts region- and/or stage-specific different effects on alveolar repair after lung fibrosis onset. Methods: Using bulk and single-cell RNAseq, multiplex IHC and spatial transcriptomics in IPF lungs, we assessed PDGFRA and B expression and mapped topographic proximity of its expressing cells to damaged basal and alveolar epithelial progenitors in fibrotic areas of different disease severity (early vs advanced). To determine the role of PDGF signaling axis after fibrosis onset, we evaluated the effect PDGFR inhibition with Imatinib or by conditional knockout of Pdgfra during the fibrosis phase of the bleomycin injury model on lung fibrosis. Results: Bulk RNAseq comparing IPF tissues with histologic evidence of early and advanced fibrosis with normal control lungs shows that PDGFRA expression is lower in IPF lungs and in areas with more advanced IPF. Mapping of PDGFRA and B expressing cells reveals that PDGFRA+ cells are more likely than PDGFRB+ cells juxtapositioned to IPF-relevant epithelial cell populations. In early fibrosis areas PDGFRA+ cells are juxtapositioned to SPC+KRT8+ alveolar progenitors, whereas in advanced fibrosis areas are close to SPC-KRT5+ basaloid-like progenitors. When we tested the effect of PDGFR signaling inhibition with Imatinib using previously established doses after fibrosis onset in the bleomycin model, we found that lower-dose (25 mg/kg) Imatinib does not ameliorate lung fibrosis and that higher-dose (50 mg/kg) worsens fibrotic lung injury. In contrast, conditional knockout of Pdfra in Gli1-expressing cells after fibrosis onset worsened bleomycin-induced fibrosis. Conclusions: Our study provides a more nuanced view of location and cell-type based PDGF signaling activity in human IPF, suggesting a greater complexity to the actions of PDGF signaling during fibrosis than previously thought and supporting the idea of niches for potential lung protective/regenerative input. The finding that loss of Pdgfra expression in the bleomycin model worsens fibrosis, further supports this idea. Our study also highlights the importance of treatment timing in studies designed to test antifibrotic effects.

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