Fzd2 orchestrates canonical and non-canonical Wnt signaling to regulate lung development and fibrosis.

Wnt signaling is a fundamental regulator of embryonic development and tissue regeneration, and its dysregulation contributes to diseases such as pulmonary fibrosis. However, the mechanisms by which Wnt signaling is differentially activated in lung cell populations and how it regulates lung development and disease pathogenesis remain unclear. Here, we identify distinct, spatiotemporal expression patterns of Wnt ligands and Frizzled receptors in the developing lung, with Fzd2 broadly expressed in epithelial, mesenchymal, and endothelial compartments. Using conditional knockout models, we demonstrate that Fzd2 plays cell type-specific roles through distinct Wnt pathways. Canonical Wnt/β-catenin signaling via Fzd2 is essential for endothelial proliferation and vascular development, while non-canonical Fzd2 signaling regulates mesenchymal cell proliferation and survival. Loss of Fzd2 in mesenchymal cells leads to impaired regeneration following bleomycin-induced injury, characterized by a transition from alveolar fibroblast 1 (AF1) to alveolar fibroblast 2 (AF2) cells. This transition suppresses Wnt2 expression, preventing alveolar type 2 (AT2) cell expansion and compromising alveolar regeneration. In addition, Fzd2-mediated PI3K-AKT signaling maintains the AF1 identity and restrains fibrotic AF2 transition. Together, these findings reveal that Fzd2 integrates canonical and non-canonical Wnt signaling to coordinate the crosstalk between mesenchyme, endothelium, and epithelium during lung development and repair, providing critical insights into fibroblast plasticity and potential therapeutic targets for fibrosis.