Secreted Frizzled-Related Protein 1 Controls Distal Lung Formation via Wnt and PDGF Signaling

Normal lung development is an intricate process that depends on temporally regulated mesenchymal signaling to coordinate structural maturation, cell differentiation, and extracellular matrix organization. How endogenous Wnt modulators such as secreted frizzled-related protein 1 (SFRP1), influence mesenchymal behavior in the developing lung remains incompletely understood, but a deeper understanding could reveal potential therapeutic targets relevant for neonatal lung diseases. Using a genetic Sfrp1 knockout model, we studied the role of Sfrp1 in distal lung development and mesenchymal signaling. Histological and morphometric studies were performed to compare lung developmental stages in the Sfrp1-/- and Sfrp1+/+ mice. Single cell RNA sequencing and proximity ligation in situ hybridization studies determined cell specific Sfrp1 expression in early development. Bulk RNA sequencing and pathway enrichment analysis detected differentially expressed genes in mesenchymal cells in the saccular stage of development. Ablation of Sfrp1 led to abnormal morphometry in the pseudoglandular, canalicular, saccular, and alveolar stages. Single cell RNA sequencing and proximity ligation in situ hybridization studies confirmed expression of Sfrp1 in mesenchymal cells, predominantly fibroblasts, in early development. Pathway enrichment analysis revealed changes in signaling pathways within the whole lung and PDGFR + cells in the saccular stage.These findings provide new evidence that Wnts exert their control over sacculation and alveologenesis through fibroblast signaling and differentiation. These results provide an important link between studies demonstrating Wnt signaling patterns in alveologenesis, aberrant Wnt signaling in BPD, and Sfrp1 mediated control of fibroblast differentiation after injury.